1-Hydroxymethyl-1-oxo-prostane derivatives of the E2 series

ABSTRACT

Derivatives, analogs, and congeners of prostane having a 1-(hydroxymethyl)-1-oxo-prostane structure in the E 2  series.

BACKGROUND OF THE INVENTION

Applicant is not aware of any prior art references which, in his judgement as one skilled in the prostaglandin art, would anticipate or render obvious the novel compounds of the instant invention; however, for the purpose of fully developing the background of the invention and establishing the state of the requesite art, the following references are set forth: U.S. Pat. Nos. 4,028,396, 3,849,487, and 3,813,433; Belgium Patent Specification 781978; Japanese Patent Specification 1004-151; Netherlands Patent Specification 7203126; and West German Patent Specification 2505-303.

BRIEF SUMMARY OF THE INVENTION

The first embodiment of the invention is represented by an optically active compound of the formula: ##STR1## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR2## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR3## wherein R₄ is selected from the group consisting of hydrogen and methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₇ is selected from the group consisting of C₂ -C₄, R₈ is selected from the group consisting of C₁ -C₂ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl, p is an integer from 0 to 3, and q is 1 or 2; the racemic mixture thereof; and the mirror image thereof.

A first preferred embodiment of the first embodiment consists of these compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR4##

A second prefered embodiment of the first embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR5## wherein R is as previously defined.

A first further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR6## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previously defined.

A second further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR7## wherein R₇, p and q are as previously defined.

A still further prefered embodiment of the second further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR8## wherein p and q are as previously defined.

A first further prefered embodiment of the second prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR9## wherein R₄, R₅, R₆, R₈, and R₁₁ are as previously defined.

A second further prefered embodiment of the second prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR10## wherein R₇, p and q are as previously defined.

A still further prefered embodiment of the second further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R is a moiety selected from the group consisting of ##STR11## wherein p and q are as previously defined.

The second embodiment of the invention is represented by an optically active compound of the formula: ##STR12## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR13## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR14## wherein R₄ is selected from the group consisting of hydrogen and methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selected from the group consisting of C₂ -C₄, R₈ is selected from the group consisting of C₁ -C₂ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl, p is an integer from 0 to 3, and q is 1 or 2; the racemic mixture thereof and the mirror image thereof.

A first prefered embodiment of the second embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR15##

A second prefered embodiment of the second embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR16## wherein R is as previously defined.

A first further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR17## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previously defined.

A second further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁ R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR18## wherein R₇ p and q are as previously defined.

A still further prefered embodiment of the second further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f as previously defined; and R is a moiety selected from the group consisting of ##STR19## wherein p and q are as previously defined.

The third embodiment of the inventor is represented by an optically active compound of the formula: ##STR20## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R is a radical selected from the group consisting of ##STR21## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR22## wherein R₆ is selected from the group consisting of C₃ -C₆ alkyl, R₇ is selected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consisting of C₁ -C₄ alkyl; the racemic mixture thereof; and the mirror image thereof.

A first prefered embodiment of the third embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR23##

A second preferred embodiment of the third embodiment consists of these compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR24## wherein R is as previously defined.

A first further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined, and R₂ is the moiety selected from the group consisting of ##STR25## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previously defined.

A second further embodiment of the first preferred embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR26## wherein R₇ is as previously defined.

A still further prefered embodiment of the second further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR27## wherein R₇ is as previously defined.

A first still further prefered embodiment of the first ruther prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR28## wherein R₆, R₁₁ and R₁₂ are as previously defined.

A second still further prefered embodiment of the first further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR29## wherein R₁₀ and R₁₁ are as previously defined.

A first further prefered embodiment of the second prefered embodiment consists of the compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined, and R₂ is a moiety selected from the group consisting of ##STR30## wherein R₆, R₁₀, R₁₁, and R₁₂ are as previously defined.

A second further prefered embodiment of the second prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR31## wherein R₇ is as previously defined.

A still further prefered embodiment of the second further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR32## wherein R₇ is as previously defined.

A first still further prefered embodiment of the first further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₂ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR33## wherein R₆, R₁₁ and R₁₂ are as previously defined.

A second still further prefered embodiment of the first further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR34## wherein R₁₀ and R₁₁ are as previously defined.

The fourth embodiment of the invention is represented by an optically active compound of the formula: ##STR35## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR36## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR37## wherein R₆ is selected from the group consisting of C₃ -C₆ alkyl, R₇ is selected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consisting of C₁ -C₄ alkyl; the racemic mixture thereof; and the mirror image thereof.

A first prefered embodiment of the forth embodiment consists of those compounds wherein f, R₂, and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR38##

A second prefered embodiment of the forth embodiment consists of those compounds wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR39## wherein R is as previously defined.

A first further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁ R₃, C₁₃ -C₁₄ and f are as previously defined, and R₂ is a moiety selected from the group consisting of ##STR40## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previously defined.

A second further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR41## wherein R₇ is as previously defined.

A still further prefered embodiment of the second further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR42## wherein R₇ is as previously defined.

A first still further prefered embodiment of the first further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR43## wherein R₆, R₁₁ and R₁₂ are as previously defined.

A second still further prefered embodiment of the first further prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR44## wherein R₁₀ and R₁₁ are as previously defined.

The fifth embodiment of the invention is represented by an optically active compound of the formula: ##STR45## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R is a radical selected from the group consisting of ##STR46## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR47## wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof; and the mirror image thereof.

A first prefered embodiment of the fifth embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR48##

A second prefered embodiment of the fifth embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR49## wherein R is as first previously defined.

A further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined and R₂ is a moiety selected from the group consisting of ##STR50## wherein R₁₁ is as previously defined.

A second further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR51## wherein R₆ and R₈ are as previously defined.

A first further prefered embodiment of the second prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR52## wherein R₁₁ is as previously defined.

A second further preferred embodiment of the second prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR53## wherein R₆ and R₈ are as previously defined.

The sixth embodiment of the invention is represented by an optically active compound of the formula: ##STR54## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR55## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR56## wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof; and the mirror image thereof.

A first prefered embodiment of the sixth embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR57##

A second prefered embodiment of the sixth embodiment consists of those compounds wherein f, R and R₃ are as previously defined C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR58## wherein R is as previously defined.

A first further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁ R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR59## wherein R₁₁ is as previously defined.

A second further prefered embodiment of the first prefered embodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR60## wherein R₆ and R₈ are as previously defined.

The seventh embodiment of the invention is represented by an optically active compound of the formula: ##STR61## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R is a radical selected from the group consisting of ##STR62## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR63## wherein x is a divalent radical selected from the group consisting of ##STR64## wherein R₅ is selected from the group consisting of C₁ -C₇ alkyl, hydrogen and a phenoxy group optionally substituted from the group consisting of halogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is a trivalent radical selected from the group consisting of ##STR65## Z is a divalent radical selected from the group consisting of --O and --CH₂ --, m is zero or an integer from 1 to 4, inclusive, n is zero or an integer from 1 to 4 inclusive, with the proviso that the sum of m and n has the value of 1 to 4, s is zero or the integer 1, t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof; and the mirror image thereof.

A first prefered embodiment of the seventh embodiment consists of those compounds wherein f, R₂, and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR66##

A second prefered embodiment of the seventh embodiment consist of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR67## wherein R is as previously defined.

The eighth embodiment of the invention is represented by an optically active compound of the formula: ##STR68## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR69## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR70## wherein X is a divalent radical selected from the group consisting of ##STR71## wherein R₅ is selected from the group consisting of C₁ -C₇ alkyl, hydrogen and a phenoxy group optionally substituted from the group consisting of halogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is a trivalent radical selected from the group consisting of ##STR72## Z is a divalent radical selected from the group consisting of --O and --CH₂ --, m is zero or an integer from 1 to 4, inclusive, n is zero or an integer from 1 to 4, inclusive, with the proviso that the sum of m and n has the value of 1 to 4, s is zero or the integer 1, t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof; and the mirror image thereof.

A first prefered embodiment of the eight embodiment consists of those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR73## A second prefered embodiment of the eight embodiment consists of those compounds wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR74##

DESCRIPTION OF THE INVENTION

The compounds of this invention are administered in various ways for various purposes, e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, bucally, sublingually, topically and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic suspensions are preferred. For subcutaneous or intramuscular injection, sterile suspensions of the compounds in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used. On certain occasions it may be advantageous to administer the compounds of this invention as clathrate compounds with substances such as α-cyclodextrin.

The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrine-induced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstrom, et al., J. Biol. Chem., 238, 3555 (1963) and Horton, Experientia, 21, 113 (1965) and references cited therein. All of the so called natural prostaglandins are derivatives of prostanoic acid: ##STR75## The hydrogen atoms attached to C-8 and C-12 are in trans-configuration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this invention include all possible optical isomers and racemates.

The configuration of substituents on the prostaglandin molecule are designed to be in the α-configuration if they lie beneath the plane of the molecule as drawn above and are designated with a--bond. Those substituents which lie above the plane of the molecule as drawn above are designated β and are represented by a bond.

The compounds of this invention which have the structure as shown in formula (A) wherein T, Z, R₃, Y, m, n, s and X are as herein above defined are said to be in the same configuration as the natural prostaglandins with respect to the configurations at C₈, C₁₁ and C₁₂ and are designated by the prefix nat. The enantiomer, represented by formula (B) is said to be in the mirror image or ent configuration. A substituent at C₁₁ drawn with a dotted line (C₁₁ --R₃) is said to have a α configuration; a solid line (C₁₁ --R₃) indicates a β configuration. The configuration at Y and X will be expressed in terms of R and S as is understood in the art. For example, the compound represented by formula (C) is named nat-15S,16S-11α,15-dihydroxy-1-(hydroxymethyl)-1,9-dioxo-15-16-trimethylene-13-trans-prostene; its enantiometer (formula D) is named ent-15R,16R-11α,15-dihydroxy-1-(hydroxymethyl)-1,9-dioxo-15,16-trimethylene-13-trans-prostene. The racemate [1:1 mixture of (C) and (D)] is named nat-15S,16S-(and) ent-15R,16R)11α,15-dihydroxy-1-(hydroxymethyl)-1,9-dioxo-15,16-trimethylene-13-trans-prostene. In a similar manner, the compounds represented by formulae (E) to (J) have the configurations shown below. ##STR76##

In each of the above formulae (C to J) the hydroxy group at C₁₁ is named "-11α-hydroxy".

The novel compounds of this invention can be prepared by a novel 1,4-conjugate-addition procedure involving treatment of the ether blocked cyclopentenone such as (129) or (111) with a lithio-cuprate reagent such as (117), (118), or (119) prepared as illustrated in Flowsheets A thru N.

The 1,4-conjugate-additon procedure is described hereinbelow in Flowsheet N. The preparation of the various requisite 1-iodo-trans-1-alkenyl or 1-tributystannyl-trans- 1-alkenyl derivative is illustrated in Flowsheets A-H and the novel and important methods of preparation of the 4-hydroxycyclopentenones embracing the 1-(hydroxymethyl)-1-oxo α chain is described in connection with Flowsheets I-M. ##STR77## wherein f' is one or two inclusive.

In accordance with the scheme as outlined hereinavbove in Flowsheet A, carbethoxycyclobutane or carbethoxycyclopentane is converted to its enolate anion (2) by treatment with a strong base such as lithium cyclohexylisopropylamide, prepared from the corresponding amine and n-butyl lithium (hexane solution) in a solvent, such as anhydrous tetrahydrofuran, at very low temperatures, such as -78° C. The resulting enolate anion (2) is then alkylated with R₆ 3-X (3) to provide (4), the ester group of which is reduced to alcohol (5) by reaction with 2 equivalents of diisobutyl aluminum hydride, lithium aluminum hydride or the like. Oxidation of alcohol (5) with dipyridine chromium oxide complex ["Reagents for Organic Synthesis", L. F. Fieser and M. Fieser, John Wiley and Sons, Inc., New York, 4, 215 (1974)], prepared in situ in methylene chloride solution, provides the corresponding aldehyde (6), which can also be obtained directly from ester (4) by partial reduction with one equivalent of diisobutyl aluminum hydride at -78° C., but the former two-step procedure is preferable. Reaction of aldehyde (6) with lithium acetylide ethylene diamine complex provides the 3-hydroxy-1-alkyne (7), which is converted to its trimethylsilyl ether in the usual manner. The silylated derivative is then treated with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The reulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give the 1-iodo-3-trimethylsilyloxy-4,4-methylene-1-alkene (8). Also, the above sequences of reactions can be accomplished, as shown in Flowsheet A, using R₉ CH₂ X where R₉ is a phenyl group. ##STR78##

In accordance with the scheme as outlined hereinabove in Flowsheet B, 1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne (9) is treated with n-butyllithium at -78° C. and then with a freshly prepared solution of zinc iodide in anhydrous tetrahydrofuran, also at -78° C. Reaction of aldehyde (10) with the resulting reagent then provides the 4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11). This reaction procedes with great stereoselectivity and the product (11) is in the erythro configuration. [For additional information concerning this reaction see the examples which follow and F. Mercier, R. Epstein and S. Holland, Bull. Soc. Chim. France, 690(1972).

The tetrahydropyranyl group in (11) is removed on weak acid treatment and the resulting erythro diol (12) can be reblocked by treating with an appropriate aldehyde or ketone ##STR79## in the presence of strong acid catalyst in the usual way to give the ketal or acetal (13). Acetone is a useful ketone for this purpose and the product (13) is then a 3,4-isopropylidenedioxy-1-alkyne. It is also possible to utilize silyl blocking groups (introduced after removal of the 1-trimethylsilyl group) to ultimately give the vinyl iodides (16) or (17). Weak base treatment of (13), for example heating for about one hour in refluxing methanol with potassium carbonate, results in disilylation to give (14). The 1-alkene (14) is converted to the corresponding 1-iodo-trans-1-alkene (15) by treatment with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures form 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give (15).

For the preparation of the threo derivatives, the 4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11) is acetylated to provide the corresponding 4-acetoxy derivative (18). The tetrahydropyranyl group is preferentially hydrolized with weak acid to (19), which is then tosylated in the usual manner to afford the erythro-3-tosyloxy-4-acetoxy-1-alkyne (20). Solvolysis of (20) under essentially neutral conditions by heating in aqueous tetrahydrofuran in the presence of an insoluble acid-acceptor, such as calcium carbonate, results in inversion of C₃, furnishing the threo-3-hydroxy-4-acetoxy-1-alkyne (21), which is then deblocked with aqueous base to give the threo-3,4-diol (22). Diol (22) is converted to an acetal or ketal (23) [or silyl derivatives as in (16) or (17)] and thence to the 1-iodo-trans-1-alkene (16) as described hereinabove wherein Ra is lower alkyl (C₁ to C₃).

For the preparation of the 16-alkoxyprostanoic acids of this invention, the erythro-4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11) is desilylated by methanol-potassium carbonate treatment and the resulting (25) is alkylated to give the 4-alkyoxy-3-tetrahydropyranyloxy-1-alkyne (26). A useful procedure for this last step involves treatment of (25) with a molar equivalent of sodium hydride to give the 4-alkoxide which is then alkylated with the appropriate alkylating agent, for example methyl iodide. The 4-alkoxy-1-alkyne (26) is then converted to the corresponding 1-iodo-trans-1-alkene (27) as described hereinabove for the preparation of (15). If desired the tetrahydropyranyl blocking group in (27) can be hydrolyzed (weak acid) and the resulting free 3-ol corresponding to (27) converted to the 3-trimethylsilyloxy derivative (28), all in the usual manner wherein Ra is lower alkyl (C₁ to C₃).

For the threo series, the tetrahydropyranyl group in erythro-4-alkoxy-1-alkyne (26) is cleaved and the resulting 3-hydroxy-4-alkoxy-1-alkyne (29) is tosylated to give the erythro-3-tosyloxy-4-alkoxy-1-alkyne (30). Sn₂ displacement reaction with (30) with reagents such as tetrahydroammonium formate results in inversion to the threo derivative (31) saponification of which provides threo-3-hydroxy-4-alkoxy-1-alkyne (32). Trimethylsilylation followed by the vinyl iodide conversion procedure described hereinabove furnishes the threo-1-iodo-1-alkene (33) wherein Rd is hydrogen or lower alkyl (C₁ to C₃).

The 15-alkyl and/or 16-alkyl derivatives of this invention can be prepared by substituting ##STR80## for (9) and/or ##STR81## for (10) (R'₅ =lower alkyl of 1 to 3 carbons) in Flowsheet B.

In accordance with the procedure as outlined in Flowsheet C, an aldehyde (34) is treated with propargylic magnesium halide to form the homopropargylic alcohol (35), which is converted to its trimethylsilyl ether in the usual manner. The silylated derivative is then treated with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperature from 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are added simultaneously to a sodium hydroxide to give the 1-iodo-4-trimethylsilyloxy-trans-1-alkene (36), precursors for 16-hydroxy-prostaglandin.

The trimethylsilyl protecting group is removed with mild acid and the resulting vinyl iodide alcohol is oxidized with pyridinium chlorochromate to provide the 1-iodo-4-oxo-trans-1-alkene (37), which upon treatment with a Grignard reagent (R₁₃ MgX) provides the 1-iodo-4-hydroxy-trans-1-alkene, which is silylated in the usual manner to provide the silyl ether (38) wherein R₁₁ ' is lower alkyl (C₃ to C₇) or lower alkenyl group (C₃ to C₅) and R₁₃ is vinyl, cyclopropyl or ethyl. ##STR82##

A more preferred method for the preparation of vinyllithium precursor is also described in Flowsheet C. Treatment of the requisite carboxylic acid (39a or 39) with the appropriate organolithium reagent (R₁₃ Li or R₁₁ 'Li respectively), wherein R₁₁ ' and R₁₃ are hereinabove defined, give the corresponding ketone (40) which upon treatment with propargylic magnesium halide provides the homopropargylic alcohol (41) which is converted to the trans vinylstannyl derivative by sequential treatment with chlorotrimethylsilane and tri-n-butyltin hydride. Treatment of the vinylstannyl reagent (42) with n-butyllithium at a temperature of -10° C. to -78° C. generates the corresponding vinyllithium reagent. ##STR83##

In accordance with Flowsheet D hereinabove, the precursors for other 16-hydroxy prostaglandins are prepared by treating an appropriate aldehyde or ketone (43) with a propargylic magnesium halide to yield the requisite homopropargylic alcohol (44). The alcohol is protected as a tritylether (45) (for secondary alcohols) or as a trimethylsilyl ether (45) (for tertiary alcohols). These ethers are then converted to the appropriate trans-vinyliodide (46) by treatment with disiamylborane generated in situ from 2-methyl-2-butene, sodium borohydride, and boron trifluoride, followed by treatment with trimethylamine oxide and then iodine and sodium hydroxide, wherein R₁₅ is hydrogen, methyl or ethyl; Z is O--C(C₆ H₅)₃ when R₁₅ is hydrogen and Z is O--Si(CH₃)3 when R₁₅ is methyl or ethyl; R₁₄ is selected from the group comprising lower alkyl (C₃ to C₅), lower 1-alkenyl (C₃ to C₅), ##STR84## wherein R₇ is as described above with the proviso that when R₁₄ is ##STR85## then R₁₅ must be hydrogen. ##STR86##

The preparation of the precursors for the synthesis of 16-aryloxy congeners is described in accordance with Flowsheet E hereinabove. The aryl esters (49) are prepared by esterifying the commercially available acids or by treatment of ethyl bromoacetate with the appropriate phenol. The ester (49) is carefully reduced to the aldehyde (50) which upon treatment with lithium acetylide provides the propargylic alcohol (51). Treatment of the alcohol (51) with chlorotrimethylsilane followed by tri-n-butyltin hydride furnishes the requisite vinylstannyl derivative (53). Similar treatment starting with substituted hydrocinnamaldehyde (50a) provides the respective vinylstannyl derivative (53a).

The preparation of the precursors for the synthesis of secondary 15-hydroxy congeners are described in the literature. The preparation of the precursor for 15-methyl-15-hydroxy is described in Flowsheet F hereinbelow. In accordance with Flowsheet F, an acid chloride, wherein R₅ is hereinabove defined, is treated with acetylene and aluminum trichloride to provide the vinylchloride (55) which upon treatment with sodium iodide furnishes the vinyliodide (56). Treatment of (56) with methylmagnesium halide followed by chlorotrimethylsilane gives the requisite protected vinyliodide (57) ##STR87##

The precursors for the novel compounds of this invention which have a β chain represented by Formuler K ##STR88## wherein s, y, m, n, and X are herein above defined is shown in Flowsheet G and Flowsheet H. ##STR89##

In accordance with the scheme as outlined hereinabove in Flowsheet G a ketone (58) is reacted with a Grignard reagent (59) such as acetylene magnesium chloride (59, s=0) or propargyl magnesium bromide (59, s=1) to give the acetylenic alcohols (60). In those cases where X is not --CH₂ -- two isomeric acetylenic alcohols are formed. These isomers can be separated by procedures well known to the art including fractional crystallization, fractional distillation and various chromatographic procedures. The individual isomers can then be carried through the remaining reactions outlined in Flowsheet G.

The acetylenic alcohol (60) is converted to its trimethylsilyl ether in the usual manner. The silylated derivative (61) is then treated with diisomaylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution is tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give the 1-iodo-3-trimethylsilyloxy-trans-1-alkene (62).

(63) in turn is readily prepared by the addition of tri-n-butyl tin hydride to the acetylene (61) in the presence of bisazoisobutyronitrile followed by vacuum distillation at a high enough temperature (about 170° C.) to isomerize any of the cis-vinyl tin compound to the trans-vinyl tin compound.

Certain of the ketones (67) of this invention are prepared as indicated in Flowsheet H below: ##STR90## wherein n and m are as hereinabove defined and the moiety ##STR91## represents a phenoxy group which is optionally substituted with one or more halogen, trifluoromethyl, and lower alkoxy (C₁ to C₄) groups.

As indicated in Flowsheet H the reaction of an epoxide (64) with a substituted or unsubstituted phenol (65) in the presence of a catalytic amount of aqueous sodium hydroxide and a phase transfer catalyst such as methyl tricapryly ammonium chloride and the like at 70°-80° C. gives the phenoxy substituted alcohol (66) which in turn is oxidized with an oxidizing reagent such as pyridinium chlorochromate in methylene chloride to give the phenoxy substituted ketone (67) This ketone (67) is then carried through the reactions shown in Flowsheet G above.

The other ketones (58) used in this invention are known in the literature or can be made by procedures well known to the art [G. Lardelli, U. Lamberti, W. T. Walles and A. P. de Jonge, Rec. Trav. Chem. Pays-Bas, 86 481 (1967); Ng. Ph. Buu-Hoi, T. B. Loc and Ng. Dat Xuong., Bull. Soc. Chem. France, 174 (1958); and G. H. Posner, Organic Reactions, 19, 1 (1972)].

The preparation of the cyclopentenones of this invention containing the hydroxyketone feature (68) wherein Z is hereinabove defined and R₃ ' is hydrogen or a hydroxy group can be accomplished in several ways one of which involves the conversion of the corresponding cyclopentenone containing a carboxylate function (69) to the respective hydroxyketone analog (68). ##STR92## Most of the cyclopentenone carboxylic acids (69) required for the purposes of this invention have been described in the literature or can be prepared by procedures quite analogous to those already described. Appropriate references are provided in the examples which follow. The synthesis of certain non-reference requisite cyclopentenone carboxylic acids (69) is also described herein.

The preparation of the requisite 4-hydroxy-thiacyclopentneones (75) is described in Flowsheet I. In accordance with Flowsheet I which is hereinbelow described, treatment of 2-furyllithium (70) with a ω-chloroaldehyde (71) provides the chloroalcohol (72). Treatment of the chloroalcohol (72) with ethylmercaptoacetate furnishes the hydroxyester (73) which upon hydrolysis with sodium formate/formic acid provides the 3-hydroxy-cyclopentenone (74). Treatment of the cyclopentenone (74) with sulfuric acid provides the required 4-hydroxy-cyclopentenone (75). ##STR93##

The conversion of the cyclopentenone carboxylic acid (69) to the respective hydroxyketone analogs (68) and the protection of these compounds for a conjugate addition reaction is described hereinbelow in Flowsheets J and K.

For the preparation of cyclopentenones of the type (79) wherein Z is hereinabove defined, the carboxylic acid (76) is converted to the acid chloride (77) by first forming the sodium salt with sodium hydride in tetrahydrofuran (THF) and then reacting the resulting suspension with oxalyl chloride in the presence of a catalytic amount of dimethylformamide (DMF). The resulting acid chloride (77), dissolved in ether, is then added dropwise to an ether solution containing two to three equivalents of diazomethane to produce the diazoketone (78). The diazoketone can by hydrolized to the hydroxy ketone (79) by refluxing an etheral solution in the presence of a dilute aqueous solution of sulfuric acid.

Alternatively, the acid chloride (77) can be heated with two equivalents of 1,1,2-tris-trimethylsilyloxyethylene at 90°-100° for 2 to 4 hours to produce compound (81). Compound (81) can be readily hydrolized and decarboxylated to give the hydroxyketone (79) by treatment with dilute hydrochloric acid in tetrahydrofuran (THF).

Protection of the hydroxy ketone function of 79, suitable for a conjugate addition reaction, can be accomplished in two ways. Ketalization of 79 with ethylene glycol is accomplished by refluxing a benzene or toluene solution of 79 and ethylene glycol into a Dean-Stark trap. The resulting ketal (82) is then treated with trimethylsilylchloride (TMSC1) and imidazole in dimethylformamide (DMF) to give 83 which is suitably protected for a conjugate addition reaction.

Alternatively 79 can be protected by the reaction with a mixture of 2-methoxy-1-propene (84) and 2,2-dimethoxypropane (85) in benzene in the presence of an acid catalyst such as p-toluenesulfonic acid to give the ketal 86 which is suitablely protected for a conjugate addition reaction. ##STR94##

The preparation of the 4-hydroxycyclopentenones of this invention (92) wherein Z is hereinabove defined is outlined in Flowsheet K below. The reaction of the hydroxy acid (87) with at least two equivalents of dimethyl-t-butyl-silylchloride in the presence of imidazole in dimethylformamide at 30°-40° C. gives the bis-dimethyl-t-butylsilated compound 88. The carboxylate dimethyl-t-butylsilyl group can be selectively removed by treatment with acetic acid, tetrahydrofuran and water (4:2:1) to give the carboxylic acid (89). The acid chloride (90) is prepared by first treating the acid (89) with sodium hydride in tetrahydrofuran to give the sodium salt. The resulting suspension of the sodium salt is then treated with oxalyl chloride in the presence of a catalytic amount of dimethylformamide. Alternatively the acid chloride (90) can be prepared directly by the reaction of the acid (89) or the dimethyl-t-butylsilyl ester (88) with oxalyl chloride in tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at 0° C. The slow addition of an etheral solution of the acid chloride (90) to an etheral solution of two to three equivalents of diazomethane gives the diazoketone (91) which on acid hydrolysis gives the 4-hydroxy cyclopentenone (92) containing the hydroxyketone function.

Alternatively the acid chloride (90) can be heated with at least two equivalents of 1,1,2-tris-trimethylsilylethylene at 90°-120° C. in the absence of a solvent to give compound (93) which is readily hydrolized and decarboxylated to give the 4-hydroxycyclopentenone (92) containing the hydroxyketone feature. Protecting of 92 can be accomplished by treatment with an excess of a mixture of 2-methoxy-1-propene (84) and 2,2-dimethoxypropane (85) in benzene with an acid catalyst such as p-toluenesulfonic acid to give the bis-ketal (94) which is suitably protected for a conjugate addition reaction. ##STR95##

Another preparation of the 4-hydroxycyclopentenones of this inventon which contain a cis double bond in the potential α chain (109) is shown hereinbelow in Flowsheet L wherein g is as hereinabove defined. As illustrated in Flowsheet L there are three methods available to prepare the important intermediate 98. The reaction of the ω-bromo carboxylic acid (95) with oxalyl chloride in an inert solvent such as benzene gives the acid chloride (96). Addition of the acid chloride (96) in ether to an etheral solution of diazomethane (2 to 3 equivalents) yields the diazoketone (97) which can be hydrolized in a two phase system consisting of ether and dilute sulfuric acid to the hydroxyketone (98). Alternatively the acid chloride (96) can be treated with an excess of 1,1,2-tris-trimethylsilyloxyethylene in the presence of a catalytic amount of stannic chloride in the absence of solvent to give compound (99) which can readily be hydrolized and decarboxylated to the desired hydroxyketone (98) using dilute hydrochloric acid in tetrahydrofuran. An alternate method to prepare (98) involves the reaction of the bromoolefin (100) with aqueous n-bromosuccinimide (NBS) in the presence of a catalytic amount of acetic acid to give a mixture of bromohydrins (101 and 102). Oxidation of the mixture of bromohydrins with an oxidizing agent such as pyridinium chlorochromate in methylene chloride gives a mixture of bromoketone (103) and bromoaldehyde (104). Refluxing this mixture with sodium formate in methanol then gives the desired intermediate (98). Protection of the ketone function of 98 is accomplished using ethylene gycol in refluxing toluene using a catalytic amount of p-toluenesulfonic acid. The ketal (103) is then reacted with dimethyl-t-butylsilylchloride and imidazole in dimethylformamide to give the fully protected compound 104. The phosphonium salt (105) is obtained by refluxing a solution of 104 and triphenylphosphine in acetonitrile. Treatment of the phosphonium salt (105) with sodium methylsulfinylmethide in dimethylsulfoxide generates a phosphonium yield which on reaction with aldehyde 106 gives 107. Refluxing a water-dioxane solution of 107 in the presence of a phosphate buffer (PH 5 to 6) gives the cyclopentenone (108). Treatment of 108 with chloral and triethylamine in ether gives (109) which on hydrolysis in a mixture of tetrahydrofuran and dilute hydrochloric acid at 50°-70° C. then gives the desired 4-hydroxycyclopentenone (110) which can be protected as described hereinabove in Flowsheet K.

Treatment of 109 with trimethylsilylchloride and imidazole in DMF gives 111 which is also suitably protected for a conjugate addition reaction. ##STR96##

The reagent 1,1,2-tris-trimethylsilyloxyethylene (80) and its use for the conversion of acid chlorides to hydroxyketone (for example 96 to 98 and 90 to 92) are claimed in this invention. The reagent preparation is described hereinbelow in Flowsheet M. The reaction of glycolic acid with 1,1,1,3,3,3-hexamethyldisilazane and trimethylsilylchoride in pyridine gives bis-trimethylsilated glycolic acid (113). Addition of (113) to a tetrahydrofuran solution of one equivalent of lithium 1,1,1,3,3,3-hexamethyldisilazane amide at -78° C. generates a lithium enolate which is trapped with trimethylsilylchloride to produce the desired reagent (80). ##STR97##

The preparation of the prostaglandin congeners of this invention are described hereinbelow in Flowsheet N wherein Z is as hereinabove defined; R₃ " is hydrogen, 2-methoxypropyl-2-oxy (--OC(CH₃)₂ OCH₃) or trimethylsilyloxy; R₃ "' is hydrogen or hydroxy; T' is the radical ##STR98## wherein R₁ is as hereinabove defined. R' is selected from the group consisting of: ##STR99## wherein R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₃, G, p, q, t, s, m, n, y, and X are as hereinabove defined.

In accordance with Flowsheet N the vinyliodide (114) is treated with either one equivalent of n-butyllithium or 2 equivalents of t-butyllithium at low temperature, preferably -30° to -70° C. in an inert solvent, eg. hexane, ether or toluene to provide the trans alkenyl-lithium reagent (116).

Alternatively, the vinyllithium reagent (116) can be prepared by treatment of a vinylstannyl derivative such as (115) with n-butyllithium at -10° to -78° C. in ether or THF.

For the preparation of the asymmetrical lithio cuprate (117) or the like, a solution of one molar equivalent of copper (I)-1-alkyne, preferably copper (I)-1-pentyne in anhydrous hexamethylphosphorous triamide preferably one to five molar equivalents, and anhydrous ether is added to one molar equivalent of the aforementioned vinyllithium solution cooled to about -78° C. After about one hour at this temperature, a molar equivalent of the requisite cyclopentenone (120) is added. After several hours at -78° C. to -20° C. the reaction mixture is quenched with aqueous ammonium chloride solution and the blocked product (121) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with the asymmetrical lithio cuprate (119) derived from vinyllithium (116) and cuprous thiophenoxide. A solution of vinyllithium (116) in ether at -78° C. is reacted with a equimolar amount of a reagent prepared by admixture, in ether at a temperature of 0° C. to -78° C., of equimolar amounts of cuprous thiophenoxide and copper (I) iodide tributylphosphonium complex. After about 30 minutes as this temperature, the lithio cuprate (119) is treated with the requisite cyclopentenone (120) as described hereinabove for the conjugate addition with 1-alkynyl lithio cuprate (117).

For the preparation of the symmetrical lithio cuprate (118) one molar equivalent of copper (I) iodide tributylphosphine complex, dissolved in anhydrous ether, is added at about -78° C. to two molar equivalents of the aforementioned vinyl lithium (116) solution in hexanes, cooled to -78° C. After about one hour at this temperature, the lithio cuprate (118) is treated with the requisite cyclopentenone (120) as described hereinabove for the conjugate addition with the 1-alkynyl lithio cuprate (117).

The procedures for conjugate addition involving organocopper reagents are well known in the art, see for example, C. J. Sih, et al., J.A.C.S. 97, 865 (1975).

All available evidence leads us to believe that the --CH═CH--R'₂ function introduced by the cuprate process occupies a position trans to the 11-oxy function. Similarly, we are led to the conclusion that in the product (121) the two side-chains attached to C₈ and C₁₂ are trans to each other. However, we are not certain of this configurational relationship in the product as it is obtained directly from the cuprate process. These products may have the side-chains in a trans- or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation 8ε. In order to ensure a trans-relationship in (121) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE₁ to a mixture containing about 90% of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature. ##STR100##

When T' is ##STR101## removal of the blocking groups from (121) to give the prostaglandin congener (122) is accomplished by treatment of (121) with a mixture of acetic acid, tetrahydrofuran and water (4:2:1) at 25° to 55° C.

When T' is ##STR102## (121) can be partially deblocked to give the ketal (123) by treatment of (121) with 0.6 N hydrochloric acid in tetrahydrofuran at room temperature for 4 to 7 hours.

In certain cases it is possible to convert the carboxylic acid function of a prostaglandin congener into a terminal hydroxymethyl ketone function as shown in Flowsheet O hereinbelow wherein Z, C_(13-C) ₁₄, and R is as hereinabove defined. Treatment of a prostaglandin congener (124) in which the hydroxy groups of the β chain are protected with a suitable group such as acetate or a dimethyl-t-butylsilyl ether with oxalyl chloride in benzene for 2 to 5 hours furnishes the acid chloride (125). Addition of the acid chloride (125), dissolved in ether, to an ether solution of at least three equivalents of diazomethane gives the diazoketone (126). Hydrolysis of the diazoketone using aqueous sulfuric acid and tetrahydrofuran at 55° C. gives the hydroxymethyl ketone analog (127). The acetate projecting group can be removed by refluxing with acidified methanol. The dimethyl-t-butylsilyl ether protecting group can be removed by treatment with aqueous hydrochloric acid in tetrahydrofuran at 25° to 60° C. ##STR103##

When the compounds of this invention are prepared from racemic starting compounds two racemates are obtained. In appropriate instances these racemates can be separated from each other by careful application of the usual chromat graphic procedures. In the more different instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19-27 (August, 1973) as well as references cited therein. Additional information concerning high speed liquid chromatography and the instruments necessary for its application is available from Waters Associate, Inc., Maple Street, Milford, Mass.]

It is also possible to prepare the compounds of this invention in their optically active forms by the conversion of the optically active 4-hydroxycyclopent-2-en-1-one carboxylic acids (128) to the optically active protected hydroxy ketone analog (129) using the methods outlined hereinabove in Flowsheet K. ##STR104##

Conjugate addition of the vinyl cuprates to (129) followed by deblocking as described hereinabove in Flowsheet N then gives the compounds of this invention in their optically active forms. Although in some cases two diastereoisomers will be formed, each optically active, they can be separated by chromatographic procedures as described hereinabove.

The preparation of optically active 4-hydroxy-cyclopent-2-en-1-ones such as (128) is described hereinbelow.

The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (130) and (131) by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereomeric mixture can then be separated by fractional crystallization, or by chromatography, or by high speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are l-α-aminoxy-γ-methylpentanoic acid hydrochloride [to give (132)], (R)-2 -aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-α-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers (130) and (131). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (132) is described in the art [R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 943 (1973)]. ##STR105##

An alternate procedure for the preparation of the 4(R)-hydroxycyclopentenone enantiomers such as (130) involves as a key step the selective microbiological or chemical reduction of trione (133) to the 4(R)-hydroxycyclopentanedione (134). A wide variety of microorganisms are capable of accomplishing this asymmetric reduction, one of the most useful being Dipodascus unincleatus. This step also can be achieved chemically by catalytic hydrogenation in the usual manner (for example, under about one atmosphere of hydrogen in methanol) using a soluble rhodium catalyst with chiral phosphine ligands, such as (1,5-cyclooctadiene)-bis-(o-anisylcyclohexylmethylphosphine)rhodium (I) tetrafluoroborate in the presence of one equivalent of organic base, such as triethylamine.

Conversion of hydroxycyclopentanedione (134) to an enol ether or enol ester, (135, E= alkyl, preferably iso-propyl; aroyl such as benzoyl; or arylsulfonyl such as 2-mesitylenesulfonyl), is accomplished by treatment, for example, with isopropyl iodide and a base such as potassium carbonate in refluxing acetone for from 15 to 20 hours, or with a base such as triethylamine and 0.95 equivalents of benzoyl chloride or a slight excess of 2-mesitylenesulfonyl chloride, in a non-prototropic solvent at a temperature of about -10° to -15° C. Reduction of (135) with excess sodium bis( 2-methoxyethoxy)aluminum hydride in a solvent such as tetrahydrofuran or toluene at low temperatures, such as -60° to -78° C., followed by mild acid hydrolysis (representative conditions: aqueous dilute hydrochloric acid, pH 2.5; or oxalic acid, sodium oxalate in chloroform) at ambient temperatures from 1 to 3 hours provides the 4(R)-hydroxycyclopentenone ester (136). The ester (136), can then be hydrolized to acid (130).

For a description of these procedures in the art see: C. J. Sih, et al, J.A.C.S., 95, 1676 (1973); J. B. Heather, et al., Tetrahedron Letters, 2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters, 2627 (1972); and R. Pappo, P. Collins, and C. Jung, Ann. N.Y. Acad. Sci., 180, 64 (1971). ##STR106##

Procedures for the preparation of the requisite cyclopentanetriones (133) are well-established in the art and generally involve the treatment of an ω-1-oxo long chain ester (137) with methyl or ethyl oxalate and a base such as sodium methoxide in methanol, followed by treatment with dilute hydrochloric acid in aqueous methanol to effect the dealkoxalxylation of the intermediate (138). See. J. Kutsube and M. Matsui, Agr. Biol. Chem., 33 1078 (1969); P. Collins, C. J. Jung and R. Pappo,Israel Journal of Chemistry, 6, 839 (1968); R. Pappo, P. Collins and C. Jung, Ann. N.Y. Acad. Sci., 180, 64 (1971); C. J. Sih, et al., J.A.C.S., 95, 1676 (1973) (see reference 7); and J. B. Heather, et al., Tetrahedron Letters, 2313 (1973) for pertinent background literature. ##STR107##

The intermediate keto esters (137) may be prepared by a variety of methods known to the art. One useful procedure is outlined below and involves alkylation of ethyl acetoacetate sodium salt (139) in the usual manner with the appropriate side-chain precursor (140, X=Cl, Br, I, preferably Br or I) followed by decarbethoxylation and reesterification. ##STR108##

The side-chain precursors (140) are commercially available where Z is --(CH₂)_(p) --, and can be prepared as described in Belgian Patent 786,215 (granted and opened to inspection Jan. 15, 1973).

Those precursors wherein Z is --(CH₂)_(t) --O--CH₂ -- can be prepared by the transformation shown directly below starting with the mono-tetrahydropyranyl derivative (143). Thus, (143) is converted to the lithium alcoholate by treatment with butyl lithium, the alcoholate is then O-alkylated with ethyl bromoacetate to provide (144), which on de-O-tetrahydropyranylation, mesylation and reaction with lithium bromide gives the required (145). (These and all the above-described transformations can be effected in the usual manner well-established in the art; pertinent examples for most of the reactions can be found in the above-cited Belgian patent 786,215.) ##STR109##

It is also possible to resolve the 4-hydroxycyclopentenone racemate (146) by microbiological means. Thus, treatment of the 4-O-alkanoyl or aroyl derivatives (147, R₁₈ = aryl or alkyl) of racemate (146) (preferably the 4-O-acetyl and 4-O-propionyl derivatives) with an approprite microorganism, preferably a Saccharomyces species e.g., 1375-143, affords preferential de-O-acylation of the 4(R)-enantiomer to give (148), which is then separated from the unreacted 4(S)-O-acyl enantiomer (149) by chromatographic procedures. After separation, mild hydrolysis of the 4(S) derivative (149) provides the 4(S)-hydroxycyclopentenone (150). [See N. J. Marsheck and M. Miyano, Biochima et Biphysica Acta, 316, 33 363 1973) for related examples.] ##STR110##

It is also possible to prepare the individual 4-hydroxycyclopentenones (148) and (150) directly by selective microbial hydroxylations of the corresponding 4-unsubstituted cyclopentenone (151). For example, with Aspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of [151, Z= (CH₂)₆ ] has been reported; see S. Kurozumi, T. Tora and S. Ishimoto, Tetrahedron Letters, 4959 (1973). Other microorganisms can also accomplish this hydroxylation. ##STR111##

The ring system of the novel compounds of this invention allow them to be characterized as follows: ##STR112##

The novel compounds of this invention possess the pharmacological activity described below as associated prostaglandins of the PGE-Type.

The known PGE compounds are all potent in causing multiple biological responses even at low doses. For example, PGE₁ and PGE₂ are extremely potent in causing vasodepression and smooth muscle stimulation, and also are potent as antilipolytic agents. Moreover, for many applications, these known prostaglandins have an inconveniently short duration of biological activity. In striking contrast, the novel prostaglandin analogs of this invention are substantially more specific with regard to potency in causing prostaglandin-like biological responses, and/or having a substantially longer duration of biological activity. Therefore, each of these novel prostaglandin analogs is surprisingly and unexpectedly more useful than one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological purposes indicated below for the latter, either because it has a different and narrower spectrum of biological activity than the known prostaglandins, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than the known prostaglandins, or because of its prolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

The 11-deoxy-PGE compunds are additionally selective in that they are at most relatively very weak stimulants of smooth muscle. The 11-deoxy PGE compounds have a further advantage in that they are much more stable and have a longer "shelf-life" than the corresponding 11 -hydroxy derivatives as described more fully hereinbelow.

Another advantage of the novel compounds of this invention, compared with the known prostaglandins, is that these novel compounds are administered effectively, orally, sublingually, intravaginally, bucally, topically, or rectally, in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

PGE₁, PGE₂, PGE₃, and dihydro-PGE₁ and their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom, et al., Pharmacol. Rev., 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGE compounds as measured, for example, in anesthetized (phenobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; stimulation of smooth muscle as shown, for example by tests on strips or guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epineephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of the PGE compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness in the case of PGE, as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and varius biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen and in the cae of the PGE compounds, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of disease and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially the PGE compounds, are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 μg to about 10 mg per ml of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGE compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastric erosion or gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 μg to about 500 μg per kg of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg per kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration. These compounds may also be useful in conjunction with various non-steroidal anti-inflammatory agents, such as aspirin, phenylbutazone, indomethacin and the like, to minimize the well-known ulcerogenic effects of the latter.

The PGE₁ compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range of about 0.005 to about 20 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

11α-Hydroxy-PGE compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE₂, for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, ro to control or prevent, uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 μg per kg of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range of 0.01 to 2 mg per kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The PGE compounds are useful as hypotensive agents to reduce blood pressure in mammals including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 μg per kg of body weight per minute, or in a single or multiple doses of about 25 to 2500 μg per kg of body weight total per day.

The PGE compounds are useful in place of oxytoxin to induce labor in pregnant female animals, including man, cows, sheep, pigs, at or near term or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.01 to 50 μg per kg of body weight per minute until or near the termination of the second stage of labor, ie., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks postmature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started.

The PGE compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and other animals. For that purpose, a PGE compound is administered systematically at a dose level in the range of 0.01 mg to about 50 mg per kg of body weight, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compounds during the first third or the second third of the normal mammalian gestation period. Accordingly they are useful as abortifacients. They are also useful for induction of menses during approximately the first two weeks of a missed menstrual period and accordingly are useful as contraceptive anti-fertility agents.

For these purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, for example, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusion of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. To illustrate a wet dressing for topical application to second and/or third degree burns or skin area 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution containing one to 500 μg/ml of the PGB compound or several times that concentration of the PGE compound. Especially for topical use, these prostaglandins are useful in combination with antibiotics, for example, gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline, with other antibacterials, for example, mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoid steroids, for example, hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each of those being used in the combination at the usual concentration suitable for its use alone.

The compounds of this invention are also useful as topical vasodilators.

The novel compounds of this invention induce the biological responses described hereinabove as associated with its particular prostaglandin type. These novel compounds are accordingly useful for the above-described corresponding purposes in the same manner as described above.

The novel PGE compounds of this invention are also useful as bronchodilators for the treatment of asthma and chronic bronchitis; as such they may be conveniently administered by inhalation of aerosol sprays prepared in a dose range of about 10 μg to about 10 mg per ml of a pharmacologically suitable liquid vehicle.

These derivatives described hereinabove are also more selective in their biological action and generally induce a more prolonged effect than the corresponding natural prostaglandins. These preparations are novel, completely unanticipated and provide distinct and important advantages.

In addition, certain of the novel compounds of this invention are useful for the preparation of other novel compounds of this invention.

It is well known that platelet aggregation inhibitors may be useful as anti-thrombotic drugs. Inhibition of platelet aggregation can be conveniently measure in vitro by monitoring changes in optical density and/or light transmission in platelet rich plasma upon addition of suitable aggregating agents such as adenosine diphosphate, epinephrine, thrombin or collagen. Alternatively, platelet aggregation can be measured in vitro using platelet rich plasma obtained at various time intervals from animals given inhibitors by an oral or parenteral route.

The compounds of the present invention exhibit the ability to inhibit platelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solution in a proportion of 40-50% human protein rich plasma. The test compounds are added at varying concentrations and after 5 minutes incubation, an aggregating agent such as adenosine diphosphate or collagen is added. The change in optical density (light transmission) is monitored by eye and inhibition is recorded as a (-) or lack of inhibition is recorded as a (+). Test compounds are considered active if they inhibit adenosine diphosphate or collagen induced aggregation at a concentration of 0.025 mg/ml or less within 5-10 minutes. For example, a compound of this invention, 1,9-dioxo-15-hydroxy-1-hydroxymethyl-13-trans-prostene, shows inhibition of platelet aggregation induced by both adenosine diphosphate and collagen at a concentration of 0.025 mg/ml.

The compounds of this invention have bronchodilator activity as determined in a test using dogs anesthetized, artificially ventilated and submitted to a continuous respiratory spasm induced by pilocarpine.

Mongrel dogs of either sex weighing between 5 and 10 kg are used. They are premedicated with morphine HCl by subcutaneous injection at 1.5 mg/kg. An intravenous perfusion of 5% (W/V) chloralose is started 1/2 hour after the morphine injection in such a way that 60 mg/kg are administered within 15 minutes. After completion, a continuous perfusion of 10 mg/kg is maintained throughout the experiment. The dogs are artificially ventilated by means of a Starling pump at a rate of 20 breaths/minute. The volume is adjusted according to the weight of the animal. [Kleinman and Radford, J. Appl. Physiol., 19, 360 (1964)]. All the measurements are made with the dogs positioned supine in a heated, V-shaped table. Curarization is obtained by succinylcholine chloride using a starting injection of 3 mg/kg lasting 3 minutes, followed by a continuous perfusion of 0.1 mg/kg/minute.

The respiratory spasm is induced by a starting injection of 400 mcg/kg of pilocarpine HCl lasting 5 minutes. An increase or decrease of the injected dose of pilocarpine HCl may occur as a fuction of the observed effect on the airways resistance. A 15 minute delay is observed before the start of a continuous perfusion of pilocarpine HCl at a dose of 4 mcg/kg/minute to maintain a constant spasm during the test.

A metallic cannula is inserted and fixed, after tracheotomy, into the upper part of the trachea. The two cophalic veins and the two femoral veiwn are catheterized to inject the various agents. The femoral artery is catheterized to measure the systemic blood pressure. An oesophageal balloon (11 cm×2.5 cm) is inserted into the lower third of the oesophagus to mesure the endothoracic pressure. The measurement of air flow is made with a Fleish pneumotachograph connected to the tracheal tube.

The transpulmonary pressure is measured as follows: The tracheal cannula is equipped with a stainless steel axial tube (1.5 mm) which is closed at its distal end and projected 2.5 cm beyond the end of the cannula. Three holes with a diameter of one mm are pierced on this latter segment. This tube, which is used to measure the tracheal pressure, is connected to one of the two chambers of a Sanborn 267 B/C, differential transducer. The other chamber is connected to the oesophageal balloon by means of a polyethylene catheter of the same length and characteristics as the balloon's.

The airflow is measured from the Fleish pneumotachograph by means of a Sanborn 270 differential transducer.

The tidal volume is obtained by electronic integration of the flow signal using an R.C. integrator.

The systemic and pulmonary blood pressures are gauged by means of Sanborn 267 B/C or 1280B pressure transducers.

An electrocardiogram is taken in lead 2. Its use is to monitor a cardiac rate-meter.

All these parameters are recorded on a Sanborn polygraph. The transpulmonary pressure and the tidal volume are also displayed as rectangular coordinates on an oscilloscope.

The airways resistance, expressed in cm of water/liter/second, is measured by subtracting from the electrical equivalent of the transpulmonary pressure, a voltage proportional to the flow so as to synchronise the pressure and volume signals on the oscilloscope [Mead and Whittenberger, J. Appl. Physiol., 5, 779 (1953)].

The value of the pulmonary elastance, expressed in cm of water/liter, is obtained by means of the same principal, i.e., an electrical signal proportioned to the volume is subtracted from the transpulmonary pressure signal, in order to optimize the pressure-flow loop on the oscilloscope.

The details of this method are described by Lulling, et al. [Med. Pharmacol. Exp., 16, 481 (1967)].

The computing operations are carried out with an anological computer which allows the direct reading, cycle to cycle, of the values of resistance and elastance.

The test compounds are administered by an Aerosol® route. The micronebulizer of a Bird Mark 7 respirator is fitted on the metallic cannula just after the pneumotachograph. The "puff" of test compound in Aerosol® is driven by a 2 kg/cm² pressure allowed to the micronebulizer just during one inspiration cycle. The micronebulizer is fitted on the respiratory tube only during the "puff". It is weighted just before and just after administration to determine the amount of test compound administered.

When administered by Aerosol® to anesthetized dogs, in whom a bronchospasm had been induced by administration of pilocarpine, 7-[3-(2-hydroxyethylthio)-2β-(3α-hydroxy-1-octenyl)-5-oxo-1.alpha.-cyclopentyl]-5-heptanoic acid methyl ester at a concentration of 32 mcg/ml caused a 60-65% inhibition of the spasm. The % inhibition of spasms induced by pilocarpine for some of the compounds of this invention is shown below in Table A.

                                      TABLE A                                      __________________________________________________________________________     Bronchodilator Activity (Pilocarpine Assay) % Inhibition of Spasm                                     % Inhibition of pilocarpine induced                                            spasm as a function of the after drug                                      Dose                                                                               administration                                                             mg/kg                                                                              5 min. 30 min.                                                                               60 min.                                   __________________________________________________________________________     1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    1-hydroxymethyl-5-cis-13-trans                                                 prostadiene        3.2 90     90     70                                        1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-hydroxymethyl-5-cis-13-trans                                                 prostadiene        3.2 80     80     66                                        1,9-dioxo-11α,15-dihydroxy-16,16-                                        trimethylene-1-hydroxymethyl-5-cis-                                            13-trans prostadiene                                                                              3.2 80     74     68                                        1,9-dioxo-15-hydroxy-15-methyl-1-                                              hydroxymethyl-13-trans prostene                                                                   3.2 37     30     30                                        1,9-dioxo-15-hydroxy-1-hydroxy-                                                methyl prostane    3.2 70     45     30                                        1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                                        3.2 92     75     55                                        1-acetoxymethyl-5-cis-13-trans                                                 prostadiene                                                                    __________________________________________________________________________

The novel compounds of the present invention have utility as bronchodilators.

Bronchodilator activity is determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylcholine by the Konzett procedure. [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968)].

In the Table B which follows, bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED₅₀ determined from the results obtained with three logarithemic comulative intravenous doses.

                                      TABLE B                                      __________________________________________________________________________     Broncodilator Activity (Konzett Assay) ED 50 mg/kg                                                Spasmogenic Agent                                                              5-Hydroxytryptamine                                                                       Histamine                                                                             Acetylcholine                             __________________________________________________________________________     1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    hydroxymethyl-5-cis-13-trans                                                                      3.81 × 10.sup. 3                                                                    3.0 × 10.sup.-3                                                                 6.4 × 10.sup.-3                     prostadiene                                                                    1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-hydroxymethyl-5-cis-13-trans                                                                    402 × 10.sup.-6                                                                     254 × 10.sup.-6                                                                 2.66 × 10.sup.-3                    prostadiene                                                                    1,9-dioxo-15-hydroxy-15-methyl-1-                                              hydroxymethyl-13-trans prostene                                                                   288 × 10.sup.-6                                                                     373 × 10.sup.-6                                                                 293 × 10.sup.-6                     1,9-dioxo-15-hydroxy-1-hydroxy-                                                methyl prostane    890 × 10.sup.-6                                                                     471 × 10.sup.-6                            1,9-dioxo-15-hydroxy-1-hydroxy-                                                methyl-13-trans prostene                                                                          19.4 × 10.sup.-3                                                                    4.8 × 10.sup.-3                                                                 >320                                      1,9-dioxo-15-hydroxy-1-acetoxymethyl-                                          13-trans prostene  2.66 × 10.sup.-3                                                                    2.16 × 10.sup.-3                                                                >3.2 × 10.sup.-3                    1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-acetoxymethyl-5-cis-13-trans                                                                    88.1 × 10.sup.-6                                                                    780 × 10.sup.-6                                                                 795 × 10.sup.-6                     prostadiene                                                                    __________________________________________________________________________

PROTOCOL FOR EVALUATION OF GASTRIC ANTI-SECRETORY AGENTS A. MODEL

Unanesthetized mongrel dogs weighing 10-15 kg are used. The animals have a surgically prepared denervated (Heidenhain) pouch which drains by gravity through a titanium cannula. These animals are trained to stand quietly in a Pavlov support. Gastric secretion is stimulated at the lowest rate giving stable secretion (25-40% of maximal) with histamine acid phosphate, 30-50 μg/kg/hr. Under such stimulation, a stable gastric secretory output can generally be maintained for a period of at least 3 hours.

Gastric juice is collected continuously during secretory studies and pooled into 15-minute collections. Determination of collection volume, pH and titratable acidity is performed Acid is determined by titrating an aliquot of gastric sample with 0.1 N NaOH to pH 7.0 using an automatic titrator.

Drugs are administered on a background of submaximal gastric secretory stimulation and the results compared with control secretory studies without the use of drug. Depending upon the duration of action of a particular drug, it may be possible for a single drug-secretory study to serve as its own control. The route of drug administration is oral administration into the main stomach. This route is easy to perform and does not interefere interfere the smooth collection of pouch gastric juice.

For example, one of the compounds of this invention 1,9-dioxo-11α,16-dihydroxy-16-methyl-1-hydroxymethyl-5-cis-13-trans- prostadiene on administration into the stomach of one of these dogs at a dose of 100 mg/kg gives the results shown hereinbelow in Table D. The data in Table D is the average of four tests in one dog.

                                      TABLE D                                      __________________________________________________________________________     Volume and titratable activity of gastric juice after adminis-                 tration of 1,9-dioxo-11α,16-dihydroxy-16-methyl-1-hydroxymethyl          5-cis-13-trans prostadiene (100 μg/kg).                                     Time after                                                                     administration                                                                         0  15  30 45 60 75 90 105                                                                               120                                           __________________________________________________________________________     Volume (ml)                                                                            3.4                                                                               2.6 1.5                                                                               1.3                                                                               0.7                                                                               0.9                                                                               1.5                                                                               1.9                                                                               2.7                                           Acid (meq/                                                                             0.43                                                                              0.35                                                                               0.22                                                                              0.20                                                                              0.09                                                                              0.13                                                                              0.21                                                                              0.27                                                                              0.40                                          15 min.)                                                                       __________________________________________________________________________

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Preparation of ethyl 2,2-trimethylenehexanoate

To a stirred solution of 27.6 g of freshly distilled N-isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran cooled to -78° C. is added at a fast rate 96 ml of 2.04 M n-butyllithium in hexane. To the resulting solution is added dropwise 25 g of ethyl cyclobutanecarboxylate. After 30 minutes the resulting solution is allowed to warm to ambient temperature, is transferred to a dropping funnel under nitrogen and is added dropwise over a period of 11/4 hours to a solution of 54 g of n-butyl iodide in 100 ml of dry dimethylsulfoxide maintaining the temperature at 16°-20° C. Stirring is continued for an additional 30 minutes. The separated salts are removed by filtration, the mother liquor is taken to a small volume and the resulting oil is diluted with hexanes. This solution is washed with 2% hydrochloric acid, saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent is removed and the residual oil is distilled to give 14.6 (41 %) of product, bp 84°-87° C. (10 mm).

EXAMPLE 2 Preparation of ethyl 2,2-tetramethylenehexanoate

In the manner described in Example 1, treatment of the lithium salt of ethyl cyclopentanecarboxylate with n-butyl iodide furnishes the subject product.

EXAMPLE 3 Preparation of 2,2-trimethylenehexan-1-ol

To a stirred solution of 20 g of ethyl 2,2-trimethylenehexanoate (Example 1) in 100 ml of dry toluene, in an argon atomsphere and cooled in an ice bath, is added dropwise 250 ml (2 molar equivalents) of 0.89 M diisobutlaluminum hydride in toluene. The resulting solution is stirred at ambient temperature for 2 hours and then poured into excess iced 5% hydrochloric acid. The organic phase is separated and washed with 5% hydrochloric acid, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 14.8 g (96%) of oil; bp 92°-93° C. 10 mm).

EXAMPLE 4 Preparation of 2,2-tetramethylenehexan-1-ol

In the manner described in Example 3, treatment of ethyl 2,2-tetramethylenehexanoate (Example 2) with 0.89 molar diisobutylaluminum hydride furnishes the subject product.

EXAMPLE 5 Preparation of 2,2-trimethylenehexaldehyde

Chromium trioxide (61.5 g), dried in a vacuum desiccator over phosphorous pentoxide, is added to an ice cold solution of 97 g of dry pyridine in one liter of dry methylene chloride. The deep red suspension is stirred for 15 minutes at 0° C. and then for 45 minutes at ambient temperature. A solution of 14.5 g of 2,2-trimethylenehexanol-1 (Example 3) in 55 ml of methylene chloride is added all at once to the suspension. A black tarry deposit is formed immediately. After stirring at ambient temperature for 15 minutes the solution is decanted from the tarry deposit which is then triturated four times with small portions of methylene chloride. The combined extracts are washed twice with ice cold 5% sodium hydroxide, ice cold 5% hydrochloric acid and finally with saturated sodium chloride solution, dried with magnesium sulfate and taken to dryness. Distillation gives 12.9 g of product; bp 69° C. (11 mm).

EXAMPLE 6 Preparation of 2,2-tetramethylenehexaldehyde

Oxidation of 2,2-tetramethylenehexan-1-ol (Example 4) with chromium trioxide-pyridine complex in the manner described in Example 5 furnishes the subject product.

EXAMPLE 7 Preparation of 4,4-trimethylene-1-octyn-3-ol

To a solution of lithium acetylide-ethylenediamine complex (9.4 g) in 90 ml of dry dimethylsulfoxide, cooled in an ice bath, is added 12.94 g of 2,2-trimethylenehexaldehyde (Example 5) in 10 ml of dimethylsulfoxide dropwise, at such a rate that the temperature is maintained at 20°-25° C. The solution is stirred at ambient temperature for 12 hours and then poured into a mixture of ice cold 2% hydrochloric acid and ether. The ether layer is separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation provides 13.53 g of product; bp 108°-109° C. (13 mm).

EXAMPLE 8 Preparation of 4,4-tetramethylene-1-octyn-3-ol

Treatment of 2,2-tetramethylenehexaldehyde (Example 6) with lithium acetylide-ethylenediamine complex in dimethylsulfoxide in the manner described in Example 4 is productive of the subject compound.

EXAMPLE 9 Preparation of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a stirred solution of 5.3 g of 4,4-trimethylene-1-octyn-3-ol (Example 7) and 5.42 g of imidazole in 32 ml of dry dimethylformamide, cooled in an ice bath under argon atmosphere is added 4.35 g of chlorotrimethylsilane. After stirring at 0° C. for 15 minutes, the solution is stirred at ambient temperature for 18 hours and then poured into 200 ml of hexanes. The solution is washed twice with ice cold water, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation furnishes 6.02 g (80%) of colorless oil; bp 110°-112° C. (14 mm).

EXAMPLE 10 Preparation of 4,4-tetramethylene-3-trimethylsilyloxy-1-octyne

Treatment of 4,4-tetramethylene-1-octyn-3-ol (Example 8) with chlorotrimethylsilane in dimethylformamide containing imidazole as described in Example 5 furnishes the subject product.

EXAMPLE 11 Preparation of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a solution of 25 g of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 9), stirred under argon atmosphere at -78° C., is added dropwise 93 ml of 2.3 M n-butyllithium in hexane at a rate to maintain the temperature below -40° C. After stirring for 40 minutes, a solution of iodine is allowed to warm to ambient temperature and 10% aqueous sodium thiosulfate solution is added until the purple color is removed. The organic phase is washed with dilute aqueous sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to afford the subject product as an oil.

EXAMPLE 12 Preparation of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-cis-octene

To a solution of 30 g of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 10) in 100 ml of methanol, under argon atmosphere is added 54 g of potassium azodicarboxylate [J. Thiele, Annalen der Chemie, 271, 127 (1892)]. To this solution is added dropwise 45 ml of acetic acid over a period of about 2 hours. The solids are removed by filtration and the mother liquor is reduced to a small volume, diluted with water and extracted with ether. The ether is evaporated and the residual oil is stirred with 250 ml of 1 M sodium bicarbonate solution. The solution is extracted several times with ether and the combined extracts are washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to furnishe the subject product as an oil.

EXAMPLE 13 Preparation of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-trans-octene

To a mixture of 4.76 g of sodiumborohydride and 23.6 g of 2-methyl-2-butene in 220 ml of dry tetrahydrofuran at -5° C. is added dropwise 23.8 g of freshly distilled borontrifluoride etherate. The resulting mixture is stirred at -5° C. to -0° C. for 2 hours and to it is added dropwise a solution of 20 g of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 12) in 20 ml of dry tetrahydrofuran. The resulting mixture is stirred at ambient temperature for 21/2 hours. The mixture is then cooled to -5° C. and there is added 44 g of trimethylene oxide portionwise over a period of 20 minutes, maintaining the temperature at 15°-20° C. The mixture is stirred at ambient temperature for 2 hours and then poured simultaneously, with a solution of 119 g of iodine in 290 ml of tetrahydrofuran, into 1490 ml of 15% aqueous sodium hydroxide solution. After stirring for 30 minutes the organic phase is separated and the aqueous phase is extracted with ether. The combined organic phase is washed with 5% aqueous sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 27 g of oily material. Chromatography on 135 g of florisil and eluting with 500 ml of hexanes furnishes 24 g of oily product which is shown to be contaminated with starting material and iodoform by infrared and thin layer chromatography. The material is purified by removing the trimethylsilyl group in the following manner. The crude product is dissolved in 350 ml of acetic acid-tetrahydrofuran-water (4:2:1) by stirring at ambient temperature for 5 minutes. The solvent is removed under reduced pressure and the residual oil containing mainly 1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene is applied to a 2" (flat) dry column containing 1200 g of Woelm silica gel. The column is developed with benzene, cut into one-inch segments and each segment is eluted with chloroform. Combination of the appropriate fractions affords 300 mg of iodomethane, 2.8 g of 4,4-trimethylene-1-octyne-3-ol, and 11.6 g of 1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene. Silylation of this material in the manner described above followed by distillation of the residual oil furnishes 13 g of pure product; bp 83°-84° C. (0.2 mm).

EXAMPLE 14 Preparation of 1-iodo-4,4-tetramethylene-3-trimethylsilyloxy-1-trans-octene

Treatment of 4,4-tetramethylene-3-trimethylsilyloxy-1-octene (Example 10) in the manner described in Example 13 furnishes the subject product.

EXAMPLES 15-20

Treatment of the lithium salt of ethyl cyclobutanecarboxylate with the alkyl halides listed in Table 1 below by the procedure described in Example 1 furnishes the 2,2-trimethylene esters of the table.

                                      TABLE 1                                      __________________________________________________________________________     Example                                                                             Alkyl Halides                                                                            Product 2,2-Trimethylene esters                                 __________________________________________________________________________     15   propyl iodide                                                                            ethyl 2,2-trimethylenepentanoate                                16   amyl iodide                                                                              ethyl 2,2-trimethyleneheptanoate                                17   hexyl iodide                                                                             ethyl 2,2-trimethyleneoctanoate                                 18   benzyl iodide                                                                            ethyl 2,2-trimethylene-3-phenylpropionate                       19   2-cyclopentyl-1-                                                                         ethyl 2,2-trimethylene-4-cyclopentylbutyrate                         ethyl bromide                                                             20   1-chloro-2-butyne                                                                        ethyl 2,2-trimethylene-4-hexynoate                              __________________________________________________________________________

EXAMPLES 21-27

Reduction of the various esters listed in Table 2 below with diisobutylaluminum hydride all in the manner described in Example 3 above is productive of the alcohols of the table.

                  TABLE 2                                                          ______________________________________                                                Starting                                                                       Esters                                                                  Example                                                                               of Example    Product Alcohols                                          ______________________________________                                         21     15            2,2-trimethylenepentan-1-ol                               22     16            2,2-trimethyleneheptan-1-ol                               23     17            2,2-trimethyleneoctan-1-ol                                24     18            2,2-trimethylene-3-phenyl-                                                     propan-1-ol                                               25     19            2,2-trimethylene-4-cyclopentyl-                                                butan-1-ol                                                26     20            2,2-trimethylene-4-hexyn-1-ol                             27     55            2,2-trimethlene-4-cis-hexen-1-ol                          ______________________________________                                    

EXAMPLES 28-34

Oxidation of the alcohols listed in Table 3 below with chromium trioxide-pyridine complex by the procedure described in Example 5 above furnishes the corresponding aldehydes of the table.

                                      TABLE 3                                      __________________________________________________________________________          Starting Alcohols                                                         Ex-  Alchohols                                                                 ample                                                                               of Example                                                                               Product 2,2 - Trimethylenealdehydes                             __________________________________________________________________________     28  21    2,2-trimethylenevaleraldehyde                                        29  22    2,2-trimethyleneheptaldehyde                                         30  23    2,2-trimethyleneoctaldehyde                                          31  24    2,2-trimethylene-3-phenylpropionylaldehyde                           32  25    2,2-trimethylene-4-cyclopentylbutyraldehyde                          33  26    2,2-trimethylenehex-4-yn-1-al                                        34  27    2,2-trimethylene-4-cis-hexene-1-al                                   __________________________________________________________________________

EXAMPLES 35-41

Treatment of the various aldehydes listed below in Table 4 with lithium acetylide-ethylenediamine complex in the manner described in Example 7 furnishes the hydroxyacetylenes of the table.

                  TABLE 4                                                          ______________________________________                                               Starting                                                                 Ex-   Aldehydes                                                                ample of Example                                                                               Product Hydroxyacetylene                                       ______________________________________                                         35    28        4,4-trimethylene-1-heptyn-3-ol                                 36    29        4,4-trimethylene-1-nonyn-3-ol                                  37    30        4,4-trimethylene-1-decyn-3-ol                                  38    31        4,4-trimethylene-5-phenyl-1-pentyn-3-ol                        39    32        4,4-trimethylene-6-cyclopentyl-1-hexyn-3-ol                    40    33        4,4-trimethylene-1,6-octadiyn-3-ol                             41    34        4,4-trimethylene-4-cis-hexene-3-ol                             ______________________________________                                    

EXAMPLES 42-48

Treatment of the various alcohols listed below in Table 5 with chlorotrimethylsilane in the manner described in Example 9 furnishes the corresponding trimethylsilyloxy acetylenes of the table.

                  TABLE 5                                                          ______________________________________                                               Starting                                                                       Alcohols                                                                 Ex-   of                                                                       ample Example  Product Trimethylsilyloxyacetylenes                             ______________________________________                                         42    35       4,4-trimethylene-3-trimethylsilyloxy-1-heptyne                  43    36       4,4-trimethylene-3-trimethylsilyloxy-1-nonyne                   44    37       4,4-trimethylene-3-trimethylsilyloxy-1-decyne                   45    38       4,4-trimethylene-3-trimethylsilyloxy-5-phenyl-                                 1-pentyne                                                       46    39       4,4-trimethylene-3-trimethylsilyloxy-6-cyclo-                                  pentyl-1-hexyne                                                 47    40       4,4-trimethylene-3-trimethylsilyloxy-1,6-                                      octadiyne                                                       48    41       4,4-trimethylene-3-trimethylsilyloxy-4-cis-                                    octene-1-yne                                                    ______________________________________                                    

EXAMPLES 49-54

In the manner described in Example 13 treatment of the various acetylenes of Table 6 below with disiamylborane, made in situ from sodium borohydride and 2-methyl-2-butene, followed by oxidation of the so formed organoborane with trimethylamine oxide followed by treatment of this product with iodine and sodium hydroxide furnishes the trimethylsilyliodovinylcarbinols of the table.

                  TABLE 6                                                          ______________________________________                                               Starting                                                                       Acetylenes                                                               Ex-   of                                                                       ample Example   Product Trimethylsilylvinylcarbinols                           ______________________________________                                         49    42        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-                                   1-trans-heptene                                                50    43        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-                                   1-trans-nonene                                                 51    44        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-                                   1-trans-decene                                                 52    45        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-                                   5-phenyl-1-trans-pentene                                       53    46        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-                                   6-cyclopentyl-1-trans-hexene                                   54    47        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-                                   1-trans-octen-6-yne                                            ______________________________________                                    

EXAMPLE 55 Preparation of ethyl 2,2-trimethylene-4-cis-hexenoate

A solution of 5 g of ethyl 2,2-trimethylene-4-hexynoate (Example 20) in 40 ml of dry pyridine is hydrogenated in a Parr apparatus using 600 mg of 5% palladium on barium sulfate. After one hour when hydrogen uptake is complete, the solution is filtered through celite and the mother liquor is taken to dryness to furnish 4 g of product as an oil.

EXAMPLE 56 Preparation of 3-tetrahydropyranyloxy-1-propyne

To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260 g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooled to 0° C. in an ice bath, is added a solution of 20 mg of para-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. The reaction mixture is stirred at 0° C. for one-half hour, and at ambient temperature for one hour. It is then poured into 200 ml of a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueousphase extracted with 100 ml of methylene chloride, the combined organic phases washed with 100 ml of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crude product, which is purified by fractional distillation, bp 71°-73° C. (14 mm) to yield 250 g (89%) of a liquid.

EXAMPLE 57 Preparation of 3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne

To a stirred -20° C. solution of 125 g (0.89 mol.) of 3-tetrahydropyranyloxy-1-propyne (Example 56) in 450 ml of ether, under a nitrogen atmosphere, is added dropwise, over one hour, a solution of 45 ml (0.89 mol.) of 2.0 N n-butyllithium in hexane. After 150 ml of dry ether is added and the mixture stirred at -20° C. for 30 minutes, a solution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of ether is added dropwise. Stirring is continued for 30 minutes at -20° C. and at ambient temperature for 18 hours. The reaction mixture is again cooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml of ether is added dropwise, followed by 90 ml of water. It is then diluted with 500 ml of water, and extracted 3 times with 300 ml of 5% sodium bicarbonate solution. The organic phase is separated, washed with 500 ml of a saturated brine solution, dried over sodium sulfate, and evaporated at 40° C. under vacuum (12 mm.). The crude product is fractionally distilled, bp 120°-125° C. (18 mm.), to yield 120 g of an oil.

EXAMPLE 58 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne

To a stirred -78° C. solution of 62 ml (124 mmol.) of a 2.0 M solution of n-butyllithium in hexane and 50 ml of dry tetrahydrofuran, under a nitrogen atmosphere is added dropwise, a solution of 24 g (113 mmol.) of 3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne (Example 57) in 35 ml of tetrahydrofuran. This solution is stirred one hour at -78° C., then a freshly prepared solution of zinc iodide (135 mmol.) in 125 ml of tetrahydrofuran [F. Mercier, R. Epstein, and S. Holand, Bull. Soc. Chim. France, 2, 690 (1972)] is added dropwise at -78° C., until the mixture turns yellow. After stirring an additional hour at -78° C., a solution of 21 g (250 mmol.) of n-valeraldehyde in 35 ml of tetrahydrofuran is added dropwise and the reaction mixture stirred for one hour at -78° C. and 18 hours at ambient temperature. It is then cooled to 0° C. and a solution of 12 ml of acetic acid in 65 ml of ether is added dropwise, followed by 75 ml of ice-water. The phases are separated and the aqueous phase is extracted twice with ether. The combined organic phases are washed 3 times with saturated sodium bicarbonate solution, until the last wash is basic, then with a saturated brine solution, dried over sodium sulfate, and evaporated to give 40 g of yellow oil. The crude product may be purified on a 4"×40" dry column of alumina, and eluted with chloroform. I.R.: neat; 3550 (OH), 2200 (C.tbd.C), 840, 750 [(CH₃)₃ Si], cm⁻¹.

EXAMPLE 59 Preparation of d,l-erythro-3,4-dihydroxy-1-trimethylsilyl-1-octyne

A solution of 19.6 g (0.066 mol) of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne (Example 58) in 55.5 ml of ethanol, 22.2 ml of acetic acid, and 22.2 ml of water is heated at reflux for 3 hours. The cooled mixture is taken to dryness and evaporated twice with benzene. The residue is taken up in hexane, washed 3 times with saturated potassium bicarbonate solution, dried with magnesium sulfate, and evaporated to give 17.0 g of crude product IR: neat, 3500-3400, broad (two OH).

EXAMPLE 60 Preparation of d,l-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne

To a stirred solution of 17.0 g (79.5 mmol.) of crude d,l-erythro-15,16-dihydroxy-1-trimethylsilyl-1-octyne (Example 59) is 33.6 ml of 2,2-dimethoxy propane at 0° C., is added 0.05 ml of 60% perchloric acid. After 30 minutes at ambient temperature, the mixture is shaken with 50 ml of hexane and 25 ml of saturated sodium bicarbonate solution. The hexane phase is separated, dried with magnesium sulfate, and evaporated to give 19.0 g of crude product.

EXAMPLE 61 Preparation of d,l-erythro-3,4-isopropylidenedioxy-1-octyne

A mixture of 19.0 g (75.0 mmol.) of crude d,l-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne (Example 60) with 95 ml of methanol and 3.0 g of potassium carbonate is refluxed for one hour. The mixture is cooled and evaporated at 50° C. (13 mm), taken up in 250 ml of benzene, and washed with 100 ml of water. The water is saturated with salt, the organic phase separated, dried with magnesium sulfate, and evaporated to give 12 g of crude product. Fractional distallation yields 7.0 g of the subject compound as a colorless oil, bp 103°-106° C. (13 mm).

IR: neat; 3300 sharp (H-C.tbd.C), 2100, (C.tbd.C), 780 (erythro configuration) cm⁻¹

nmr:_(TMS).sup.δCDCl.sbsp.3 ; 4.75 (dd., 1, C.tbd.C-CH-CH, J═2Hz, J═5Hz), 4.10 (m, 1, C.tbd.C-CH-CH-CH₂, 2.5 (d, 1, H-C C-CH), 1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂ CH₃).

EXAMPLE 62 Preparation of d,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

To a stirred 0° C. slurry of 0.852 g (0.023 mol.) of sodium borohydride and 4.21 g (0.060 mol.) of 2-methyl-2-butene in 40 ml of dry tetrahydrofuran, under an argon atmosphere, is added dropwise 4.26 g (0.030 mol.) of boron trifluoride etherate complex. A solution of 2.73 g (0.015 mol.) of d,l-erythro-3,4-isopropylidenedioxy-1-octyne (Example 61) in 5 ml of tetrahydrofuran is added dropwise, the ice bath removed, and the mixture allowed to stir at ambient temperature for two hours. It is then cooled again to 0° C., and 2.88 g (0.105 mol.) of dry trimethylamine oxide is added in portions over 30 minutes. After stirring 3 hours at room temperature, this mixture is poured simultaneously with a 0° C. solution of 2.13 g of iodine in 53 ml of tetrahydrofuran into 766 ml of a 0° C. 15% solution of sodium hydroxide in water and the whole stirred vigorously at 0° C. for 45 minutes. The organic phase is separated, the aqueous phase is extracted twice with ether, the combined organic phases are washed with a 5% solution of sodium thiosulfate, dried with magnesium sulfate, and evaporated. The crude product is chromatographed on a 2" by 40" dry column of silica gel, be eluting with chloroform, to yield 1.2 g (25%) of a yellow oil.

IR: neat; 1599 sharp, 945 ##STR113## cm⁻¹ 1

EXAMPLE 63 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A solution of 3.0 g (13.2 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne is heated at 100° C. for 15 hours with 3 ml of acetic anhydride and 10 ml of pyridien. The mixture is evaporated to dryness, dissolved in ether, washed with sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate and evaporated to give 2.5 g of the subject compound as an oil IR: neat; 2200 (C C), 1730 (C═O), 830, 760 [(CH₃)₃ Si], cm⁻¹.

EXAMPLE 64 Preparation of d,l-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

In the manner of Example 59, 2.5 g (7.4 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 63) in a solution of ethanol, acetic acid, and water is heated at 100° C. for 3 hours. After workup, the crude product is chromatographed on a 7/8"×22" dry column of silica gel, and eluted with chloroform to give 1.0 g of a yellow oil.

IR: neat; 3500 (OH), 1730 (C═O), cm⁻¹.

EXAMPLE 65 Preparation of d,l-erythro-3-paratoluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

To a solution of 7.5 g (41.0 mmol.) of d,l-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 64) in 41 ml of dry pyridine is added 11.0 g (58 mmol.) of paratoluenesulfonyl chloride and the resulting solution is stirred at 25° C. for 15 hours. The mixture is then warmed at 40° C. for one hour, and after cooling, partitioned between 500 ml of diethyl ether and 100 ml of 1.0 N hydrochloric acid. The organic phase is washed three times with 100 ml of 1.0 N hydrochloric acid, once with dilute sodium bicarbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil. The crude product is purified on a 2"×24" dry column of silica gel, and eluted with chloroform to yield a yellow oil.

IR: neat, 1730 (C═O), 1595 (aromatic) cm⁻¹.

EXAMPLE 66 Preparation of d,l-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A mixture of 15.5 g (39.0 mmol.) of d,l-erythro-3-para-toluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 65), 5.0 g of calcium carbonate, 25 ml of water and 250 ml of tetrahydrofuran is refluxed with stirring for 4 days. The mixture is cooled, 100 ml of water added and the organic phase separated. The aqueous phase is extracted with ether, the combined organic phases dried with magnesium sulfate, and evaporated. The crude product is chromatographed on a 3"×30" dry column of silica gel, and eluted with chloroform to give 7.0 g of an oil.

IR: neat; 3500, (OH), cm⁻¹.

EXAMPLE 67 Preparation of d,l-threo-3,4-dihydroxy-1-octyne

A solution of 7.0 g (28 mmol.) of d,l-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 66) in 50 ml of methanol is stirred at room temperature for 24 hours with a solution of 6.3 g (112 mmol.) of potassium hydroxide in 50 ml of water. The mixture is extracted twice with hexane, washed with 0.5 M hydrochloric acid, brine, and dried with magnesium sulfate. After evaporation, the subject compound is obtained as a yellow oil.

IR: neat, 2500 broad (2-OH), cm⁻¹.

EXAMPLE 68 Preparation of d,l-threo-3,4-isopropylidenedioxy-1-octyne

In the manner of Example 60, treatment of a solution of d,l-threo-3,4-dihydroxy-1-octyne (Example 67) in dimethoxypropane with 60% perchloric acid, and fractional distillation (12 mm) is productive of the subject compound as a colorless oil, containing 15% of d,l-erythro-3,4-isopropylidenedioxy-1-octyne (Example 60), as an impurity.

IR: neat; 810 (threo configuration).

nmr:_(TMS).sup.δ CDCl.sbsp.3 ; 4.2 (dd, 1, --C.tbd.C--CH--, J's - 2H_(z), 6H_(z)), 4.1-3.9 (m, 1, --C.tbd.C--CH--CH--CH₂ --), 2.5 (d, l, H--C═C--, J=2H_(z)), 1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂ --CH₃).

EXAMPLE 69 Preparation of d,l-threo-1-iodo-3,4-iosopropylidenedioxy-trans-1-octene

In the manner of Example 62, d,l-threo-3,4-isopropylidenedioxy-trans-1-octyne (Example 68) is treated successively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide to give the subject compound.

EXAMPLE 70

Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne

Alkaline hydrolysis of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne (Example 58) by the procedure of Example 61 is productive of the subject compound.

EXAMPLE 71 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne

To a stirred slurry of 6.0 g (150 mmol.) of a 60% oil dispersion of sodium hydride and 96 g of iodomethane, under an argon atmosphere, is added 700 ml of dry tetrahydrofuran. The stirred mixture is cooled to -20° C. and a solution of 30 g (133 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne (Example 70), is added dropwise, followed by 0.1 ml of methanol. The mixture is stirred at ambient temperature for 24 hours, 10 ml of methanol is added, and evaporated. The residue is taken up in ether, washed 3 times with water, dried over magnesium sulfate, and evaporated. The crude product is purified by fractional distillation to yield 16.3 g of a colorless oil, bp 137°-140° C. (12 mm).

EXAMPLE 72 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octen

In the manner of Example 62, 1.20 g (5.0 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne (Example 71) is treated successively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide. Chromatography on a 2"×36" dry column of silica gel and elution with chloroform is productive of 0.80 g (40%) of the subject compound as an oil.

nmr:_(TMS).sup.δ CDCl.sbsp.3 ; 7.9-6.1 (m,2, HC═CH), 4.9-4.6 (2m, 2, c═C--CH, O--CH--O), 4.3-4.0 (m, 1, c═c--CH--CH--CH₂), 3.9-3.0 (m, 6, CH₂ --O--CH, OCH₃), 1.8-1.2 (m, 12H, alkyl), 0.9 (m, 3, --CH₃).

EXAMPLE 73 Preparation of d,l-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene

A solution of 3.10 g (8.24 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octene (Example 72) in 60 ml of acetic acid, 30 ml of tetrahydrofuran, and 15 ml of water is stirred at ambient temperature for 18 hours. It is then evaporated at 70° C. under high vacuum (1.0 mm), and three times with 40 ml of toluene to give the crude product as an oil.

EXAMPLE 74 Preparation of d,l-erythro-3-trimethylsilyloxy-4-methoxy-1-iodo-trans-1-octene

To a stirred solution of 3.0 g (10.2 mmol.) of d,l-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene. (Example 73) in 11.0 ml of dry dimethylformamide and 1.90 g (28.0 mmol.) of imidazole cooled to 0° C. is added, dropwise, 1.35 g (12.5 mmol.) of trimethylsilyl chloride. The reaction mixture is stirred a further 4 hours at room temperature. It is then poured into a mixture of 100 ml of hexane and 25 ml of water, the organic phase is separated, washed twice with water once with a solution of saturated sodium chloride, dried over magnesium sulfate, and evaporated. The crude product is purified by fractional distillation to yield 2.0 g of a colorless oil, bp 82°-83° C. (0.3 mm).

IR: neat; 1602 sharp ##STR114## 840, 750 broad [(CH₃)₃ Si--], cm⁻¹.

EXAMPLE 75 Preparation of d,l-erythro-1-iodo-3,4-dihydroxy-trans-1-octene

A solution of 1.40 g (4.50 mmol.) of d,l-erythro-1-iodo-3,4-iosopropylidenedioxy-trans-1-octene (Example 62) in 30 ml of acetic acid, 10 ml of tetrahydrofuran and 10 ml of water is stirred and heated at 50° C. for five hours. It is then evaporated at 40° C. under high vacuum (1.0 mm), and twice more with 50 ml of benzene. Crystallization from 10 ml of chloroform at 0° C. is productive of 700 mg of the white crystalline subject product.

EXAMPLE 76 Preparation of d,l-erythro-1-iodo-3,4-bis-trimethylsilyloxy-trans-1-octene

To a stirred solution of 700 mg (2.40 mmol.) of d,l-erythro-1-iodo-3,4-dihydroxy-trans-1-octene (Example 75) and 800 mg (12.0 mmol.) of imidazole, in 10 ml of dry dimethylformamide at 0° C. is added dropwise 1.20 g (11.0 mmol.) of trimethylchlorosilane. The ice bath is removed, and the mixture is stirred and heated at 50° C. for five hours. It is then cooled, shaken with 50 ml of hexane and 50 ml of water, the organic layer separated and washed with 15 ml of 0.5 M hydrochloric acid, 15 ml of a saturated solution of sodium bicarbonate, dried with magnesium sulfate, and evaporated. This crude product is fractionally distilled, bp 90°-92° C. (0.40 mm) to yield 250 mg of a colorless oil.

EXAMPLE 77 Preparation of d,l-erythro-3-trimethylsilyloxy-4-ethoxy-1-iodo-trans-1-octene

Following the procedure of Example 71, ethylation using iodoethane of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne for a period of 22 hours is productive of the corresponding d,l-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-octyne. This intermediate is converted to d,l-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-iodo-trans-1-octene when treated successively with disiamylborane, trimethylamine oxide iodine, and sodium hydroxide solution after the procedure of Example 72. Acid hydrolysis by the method of Example 18 to dl,-erythro-3-hydroxy-4-ethoxy-1-iodo-trans-1-octene, followed by treatment with chlorotrimethylsilane and imidazole in dimethylformamide using the procedure of Example 74, and subsequent distillation, is productive of the subject compound.

EXAMPLES 78-82

By the method of Example 58 reaction of 1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne with n-butylithium and subsequent treatment with the aldehydes listed in Table 7, below, provides the d,l-erythro-1trimethlsilyl-3tetrahydropyramyloxy-4-hydroxy-1-alkynes of the table.

                                      TABLE 7                                      __________________________________________________________________________                    Product d,1-erythro-3-tetrahydropyranyloxy-                     Example                                                                             Starring Aldehyde                                                                        4-hydroxy-1-trimethylsilyl-1-alkyne                             __________________________________________________________________________     78   n-butanal d,l-erythro-1-trimethyisilyl-3-tetrahydropyranyloxy-4-                         -  hydroxy-1-heptyne                                            79   n-hexanal d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-1-nonyne                                                80   n-heptanal                                                                               d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-1-decyne                                                81   4-methyl-n-pentanal                                                                      d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-7-methyl-1-octyne                                       82   2-trans-n-pentenal                                                                       d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-5-trans-en                                              __________________________________________________________________________

EXAMPLES 83-87

Hydrolysis of the 3-tetrahydropyranyloxy group of the d,l-erythro- 1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynes listed in Table 8 below by the method described in Example 59, followed by conversion of the resulting d,l-erythro- 1-trimethylsilyl-3,4-dihydroxy-1-alkyne to the corresponding d,l-erythio- 1-trimethylsilyl-3,4-isopropylidenedioxy-1-alkyne by treatment with dimethoxypropane in the presence of perchloric acid by the method described in Example 60, followed by desilylation to the corresponding d,l-erythro- 3,4-isopropylidenedioxy-1-alkyne by the procedure of Example 61 followed by treatment with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solution by the method described in Example 62 provides the product d,l-erythro- 1-iodo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 8, below.

                                      TABLE 8                                      __________________________________________________________________________          Starting d,1-erythro-1-trimethyl-                                              silyl-3-tetrahydropyranyloxy-4-                                                                Product d,1-erythro-1-iodo-3,4-iso-                       Example                                                                             hydroxy-1-alkyne of Example                                                                    propylidenedioxy-trans-1-alkene                           __________________________________________________________________________     83   78              d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans-1-heptene                                 84   79              d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans-1-nonene                                  85   80              d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans-1-decene                                  86   81              d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-7-methyl-trans-1-octene                         87   82              d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans,trans-1,5-octadiene                       __________________________________________________________________________

EXAMPLEs 88-92

Acetylation of the 4-hydroxy group of the d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynes listed in Table 9 below by the method described in Example 63, followed by hydrolysis of the resulting d,l-erythro-1-trimethylsilyl- 3-tetrahydropyranyloxy-4-acetyloxy-1-alkynes to the corresponding d,l-erythro-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the method of Example 65, followed by epimerization to d,l-threo-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the method of Example 66 followed by hydrolysis by the method of Example 67 to give d,l-threo-3,4-dihydroxy-1-alkynes are converted to the corresponding d,l-threo-3,4-isopropylidenedioxy-1-alkynes by treatment with dimethoxypropane in the presence of perchloric acid by the method described in Example 68 followed by treatment with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solution by the method described in Example 62 provides the product d,l-threo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 9 below.

                                      TABLE 9                                      __________________________________________________________________________          Starting d,1-erythro-1-trimethyl-                                              silyl-3-tetrahydropyranyloxy-4-                                                                Product d,1-threo-1-iodo-3,4-iso-                         Example                                                                             hydroxy-1-alkyne of Example                                                                    propylidenedioxy-trans-1-alkene                           __________________________________________________________________________     88   78              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1-heptene                                           89   79              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1-nonene                                            90   80              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1-decene                                            91   81              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1,7-methyl-1-octene                                 92   82              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1,5-trans-1-octadiene                               __________________________________________________________________________

EXAMPLE 93 Preparation of 1-octyn-4-ol

A suspension of 24.3 g (1.0 mole) of magnesium in 90 ml of dry ether is stirred at room temperature under nitrogen with 100 mg of mercuric chloride. The reaction is initiated by the addition of 2 ml of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g (1.0 mole) of propargyl bromide and 107.7 g (1.25 mole) of valenaldehyde in 300 ml of dry ether. While the initial reaction is quite vigorous and is maintained at 30° C. only by cooling in an ice bath it may become necessary to heat the mixture to reflex temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 g of yellow oil, which is distilled through a 15 cm Vigreaux column at 18 mm. The fraction boiling at 81°-82° C. is collected (36 g) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1μ) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.

EXAMPLES 94-97

The product 1-alkyn-4-ols of Table 10 below are prepared by treatment of the aldehydes listed in Table 10 with propargyl magnesium bromide by the procedure described above in Example 93.

                  TABLE 10                                                         ______________________________________                                                                   Product                                              Example   Starting Aldehyde                                                                              1-alkyn-4-ol                                         ______________________________________                                         94        n-hexaldehyde   1-nonyn-4-ol                                         95        n-heptaldehyde  1-decyn-4-ol                                         96        n-butyraldehyde 1-heptyn-4-ol                                        97        3-cis-hexenaldehyde*                                                                           4-hydroxy-6-cis-                                                               ene-1-nonyne                                         ______________________________________                                          *M. Winter, Helv. Chim. Acta, 46, 1792 (1963).                           

EXAMPLE 98 Preparation of 4-triphenylmethoxy-1-octyne

A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [1. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g (0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue of Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).

EXAMPLE 99 Preparation of 4-triphenylmethoxy-1-hexyne

A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm-1 (triphenylmethoxy group).

EXAMPLES 100-106

The triphenylmethoxy substituted 1-alkynes listed in Table 11 below are prepared by the method of Example 98 from triphenylmethyl bromide and the corresponding hydroxy substituted 1-alkynes, appropriate literature references to which are provided in the table.

                  TABLE 11                                                         ______________________________________                                                Reference to                                                                   Starting Hydroxy Product Triphenylmethoxy                               Example                                                                               Substituted 1-Alkyne                                                                            Substituted 1-Alkyne                                   ______________________________________                                         100    Reference 1      4-triphenylmethoxy-                                                            1-pentyne                                              101    Reference 1      4-triphenylmethoxy-                                           (Example 96)     1-heptyne                                              102    Reference 1      4-triphenylmethoxy-                                                            5-methyl-1-hexyne                                      103    Reference 2      4-triphenylmethoxy-                                           (Example 94)     1-nonyne                                               104    Reference 3      4-triphenylmethoxy-                                           (Example 95)     1-decyne                                               105    Reference 4      4-triphenylmethoxy-                                                            5-ethyl-1-heptyne                                      106    Example 97       4-triphenylmethoxy-                                                            6-cis-ene-1-nonyne                                     ______________________________________                                          References:                                                                    1 G. Fontaine, et al., Bull. Soc. Chem. France, 1447 (1963).                   2 S. Abe and K. Sato, Bull. Soc. Chem. Japan, 29, 88 (1956); Chem. Abstr.      50, 13737 (1956).                                                              3 L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957);                    4 Nobuharra, Akio, Chem. Abstr., 70, 3219 (1969).                        

EXAMPLE 107 Preparation of 1-iodo-4-triphenylmethoxy-trans-1-octene

To a stirred suspension of 1.78 g (0.074 mole) of sodium borohydride in 200 ml of dry glyme at -5° C. under nitrogen is added 15.8 g (0.22 mole) of 2-methyl-2-butene and 16.2 g (0.11 mole) of boron trifluoride etherate, and the mixture is stirred for 2 hours at -5° C. 0° 0°C. A solution of 37.5 g. (0.10 mole) of 4-trityloxy-1-octyne (Example 98) in 50 ml of glyme is added to the cold solution during 5-10 minutes, and the solution is allowed to warm to 20° C. during 1.5 hours. The reaction mixture is cooled to 0° C. and 30 g (0.4 mole) of dry trimethylamine-N-oxide is added during 5 minutes. On removing the cooling bath the temperature rises to 40° C. and the mixture is kept between 30°-40° C. for 1.5 hours. The suspension is poured rapidly into one liter of ice cold 15% sodium hydroxide solution during good stirring and a solution of 80 g of iodine in 200 ml of tetrahydrofuran is added immediately. Stirring is continued for 30 minutes without further cooling and the organic layer is separated. The aqueous layer is extracted with three 200 ml portions of ether and the combined organic layers are washed successively with water, 5% sodium thiosulfate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to yield 50 g of yellow oil. The bulk of the oil is dissolved in hexane and, after decantation from a gummy solid the hexane solution is percolated through a 5.1 cm diameter column of 1500 g of alumina with additional hexane. Fractions containing the desired product are concentrated to a pale yellow oil (33 g) which has n.m.r. and infrared spectra characteristics of the desired product.

EXAMPLES 108-115

Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table 12 below with disiamylborane, prepared in situ from 2-methyl-2-butene, boron, trifluoride and sodium borohydride, followed by trimethylamine N-oxide, and then sodium hydroxide and iodine - all by the procedure described in Example 107 above furnishes the product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of the table.

                  TABLE 12                                                         ______________________________________                                                 Starting Triphenyl-                                                                             Product 1-Iodo-tri-                                           methoxy Substituted                                                                             phenylmethoxysubsti-                                  Example 1-Alkyne of Example                                                                             tuted-1-trans-alkene                                  ______________________________________                                         108      99              1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               hexene                                                109     100              1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               pentene                                               110     101              1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               heptene                                               111     102              1-iodo-4-triphenyl-                                                            methoxy-5-methyl-1-                                                            trans-hexene                                          112     103              1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               nonene                                                113     104              1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               decene                                                114     106              1-iodo-4-triphenyl-                                                            methoxy-1-trans-6-                                                             cis-nonadiene                                         ______________________________________                                    

EXAMPLES 116-124

The starting aldehydes or ketones of Table 13 below are converted to the product 1-alkyn-4-ols of the table by the procedure described in Example 93.

                  TABLE 13                                                         ______________________________________                                                Starting Aldehyde                                                       Example                                                                               or Ketone     Product 1-Alkyn-4-ol                                      ______________________________________                                         115    2-octanone    4-methyl-4-hydroxy-1-decyne                               116    trans-2-hexenal                                                                              4-hydroxy-5-trans-nonen-1-yne                             117    2,2-dimethylhexanal                                                                          5,5-dimethyl-4-hydroxy-1-nonyne                           118    z-heptanone   4-methyl-4-hydroxy-1-nonyne                               119    2,2-dimethylpentanal                                                                         5,5-dimethyl-4-hydroxy-1-octyne                           120    2-methylpentanal                                                                             5-methyl-4-hydroxy-1-octyne                               121    2-methylhexanal                                                                              5-methyl-4-hydroxy-1-nonyne                               122    2-hexanone    4-hydroxy-4-methyl-1-octyne                               123    trans-3-hexen-2-one.sup.a                                                                    4-hydroxy-4-methyl-5-trans-                                                    octen-1-yne                                               124    trans-2-pentenal.sup.b                                                                       4-hydroxy-5-trans-octen-1-yne                              124a  trans-2-heptenal.sup.b                                                                       4-hydroxy-5-trans-decen-1-yne                             ______________________________________                                          .sup.a G. Sturtz, Bull. Soc. Chim. Fr., 1967, 2477.                            .sup.b R. I. Hoaglin and D. M. Hirsh, U.S. 2,628,257; Chem. Abstr., 48,        1423e (1954).                                                            

EXAMPLE 125 Preparation of 4-methyl-4-trimethylsilyloxy-1-octyne

To a stirred solution of 75.4 g (0.537 moles) of 4-hydroxy-4-methyl-1-octyne (Example 122), 104.9 g (1.54 moles) of imidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 800 ml of hexane. The mixture is washed thoroughly with water followed by sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate, filtrated, and evaporated to give a liquid, p.m.r. spectrum, δ 1.26 (singlet, 3, CH₃), 1.92 (triplet, 1, HC), 2.30 (doublet, 2, CH₂).

EXAMPLES 126-129

The 1-alkyn-4-ols of Table 14 are converted to the product trimethylsilyl ethers of the table by treatment with chlorotrimethylsilane according to the procedure described in Example 125.

                                      TABLE 14                                     __________________________________________________________________________     Example                                                                             Starting 1-Alkyn-4-ol                                                                        Product Trimethylsilyl Ether                                __________________________________________________________________________     126  5,5-dimethyl-4-hydroxy-1-                                                                    5,5-dimethyl-4-trimethylsilyloxy-1-nonyne                        nonyne (Ex. 117)                                                          127  4-methyl-4-hydroxy-1-nonyne                                                                  4-methyl-4-trimethylsilyloxy-1-nonyne                            (Ex. 118)                                                                 128  5,5-dimethyl-4-hydroxy-1-                                                                    5,5-dimethyl-4-trimethylsilyloxy-1-octyne                        octyne (Ex. 119)                                                          129  4-hydroxy-4-methyl-5-trans-                                                                  4-methyl-4-trimethylsilyloxy-5-trans-                            octen-1-yne (Ex. 123)                                                                        octen-1-yne                                                  129a                                                                               4-hydroxy-4-methyl-1-decyne                                                                  4-methyl-4-trimethylsilyloxy-1-decyne                            (Ex. 124a)                                                                __________________________________________________________________________

EXAMPLE 130 Preparation of 1-iodo-4-hydroxy-4-methyl-trans-1-octene

To a stirred solution of 400 ml of 0.5 M bis-(3-methyl-2-butyl)borane in glyme, prepared from sodium borohydride, 2-methyl-2-butene, and boronitrifluoride etherate as in Example 107, is added 63.7 g (0.30 moles) of 4-methyl-4-trimethylsilyloxy-1-octyne (Example 125) at -10° C. The solution is stirred at ambient temperature for 2.5 hours, cooled to -10° C., and treated during 30 minutes with 158 g (2.1 moles) of solid trimethylamine oxide with cooling. The mixture is stirred at ambient temperature for 2 hours and then poured into a stirred, ice-cold solution of 15% aqueous sodium hydroxide; the stirred mixture is treated immediately with a solution of 426 g (1.68 moles) of iodine in 1100 ml of tetrahydrofuran. After 4 hours the mixture is extracted with ether. The extract is washed successively with water, aqueous sodium thiosulfate, and brine and dried over magnesium sulfate. The extract is concentrated, and the residue is subjected to chromatography on silica gel with hexane to provide an oil, p.m.r. (CDCl₃): δ 1.18 (singlet, 4--CH₃ group).

EXAMPLES 131-134

The 4-trimethylsilyloxy-1-alkynes of Table 15 are converted to the 4-hydroxy-1-iodo-trans-1-octenes of the table by the procedure described in Example 130.

                  TABLE 15                                                         ______________________________________                                                   Starting 4-Tri-                                                                methylsilyloxy-                                                                1-octyne of  Product 4-Hydroxy-1-iodo-                               Example   Example      trans-1-octene                                          ______________________________________                                         131       126          1-iodo-5,5-dimethyl-4-hy-                                                      droxy-trans-1-nonene                                    132       127          1-iodo-4-methyl-4-hydroxy-                                                     trans-1-nonene                                          133       128          1-iodo-5,5-dimethyl-4-hy-                                                      droxy-trans-1-octene                                    134       129          1-iodo-4-methyl-4-hydroxy-                                                     trans,trans-1,5-octadiene                                134a      129a        1-iodo-4-methyl-4-hydroxy-                                                     trans-1-decene                                          ______________________________________                                    

EXAMPLE 135 Preparation of 1-iodo-4-methyl-4-trimethylsilyloxy-trans-1-octene

To a stirred mixture of 24.5 g (55.6 mmoles) of 1 -iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 mmoles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68° C. (0.07 mm).

EXAMPLES 136-139

The 1-iodo-4-hydroxy-trans-1-alkenes of Table 16 are converted to the product trimethylsilyl ethers of the table according to the procedure described in Example 135.

                  TABLE 16                                                         ______________________________________                                                Starting 1-Iodo-4-                                                             hydroxy-trans-1-                                                                               Product Trimethylsilyl                                  Example                                                                               alkene of Example                                                                              Ether                                                   ______________________________________                                         136    131             1-iodo-5,5-dimethyl-4-                                                         trimethylsilyloxy-                                                             trans-nonene                                            137    132             1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans-1-                                                        nonene                                                  138    133             1-iodo-5,5-dimethyl-4-                                                         trimethylsilyloxy-                                                             trans-1-octene                                          139    134             1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans,-                                                         trans-1,5-octadiene                                      139a   134a           1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans-1-                                                        decene                                                   139b   134b           1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans-1-                                                        decene                                                  ______________________________________                                    

EXAMPLE 140 Preparation of 4-benzoyloxy-1-octyne

To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue is ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λ max. 3240 (terminal acetylene) and 1730 cm⁻¹ (benzyloxy group).

EXAMPLE 141 Stereoselective Hydrolysis of Racemic 4-benzoyloxy-1-octyne by Rhizopus arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shake flasks (250 ml Erlenmeyer). Each flask contains 50 ml of a medium consisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor in water with pH adjusted to 7.0. A total of 14 such flasks are incubated on a rotary shaker at 28° C. After 72 hours incubation, 50 mg of racemic 4-benzoyloxy-1-octyne (Example 135 ) in 0.1 ml of acetone is added to each flask. After 28 hours the flasks are harvested and worked up by extraction of the whole mash with an equal volume of chloroform. The combined extracts are dried over magnesium sulfate chromatographed concentrated. The resulting oil is chromatographe on a column of silica gel with hexane progressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg of colorless oil, identical to 4-benzoyloxy-1-octyne, [α]_(D) ²⁵ =5±1.0° (C=0.91, ethyl acetate). This compound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg of colorless oil, identical to 4-hydroxy-1-octyne, [α]_(D) ²⁵ =- 17±1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher fungus which grows steadily on a variety of artificial media at 20°-25° C. In this study of the taxonomic aspects of the culture, Petri dishes of potato-dextrose, malt extract, and cornmeal agars were inoculated and incubated at ambient room temperature for 10 days. Observations of cultural and morphological characteristics are recorded in the description below:

Colonies on Petri dishes of potato-dextrose agar growing rapidly, covering the agar surface in 3-5 days and producing a thick, loose mat of grayish mycelium. Colony surface characterized by abundant black sporangia. Colony reverse grayish white. Colonies on malt extract agar growing rapidly, covering the agar surface in 3-5 days. Mycelial mat thick, grayish-yellow. Colony surface becoming brownish-black from masses of sporangia. Colony reverse yellowish. Colonies on cornmeal agar very thin, whitish; spreading across agar surface. Cultures transparent with relatively few sporangia produced. Visibility of micromorphology is good on this mediu. Rhizoids produced sparingly among stoloniferous hyphae. Generally two to three sporangiophores arose from rhizoids. Walls of sporangiophores olive brown, 14.0-20.0 μm in width at base, tapering slightly to apex; 0.5-1.5 mm in length Sporangiophores terminated by spherical sporangia, 130-225 μm in diameter. Columellae hemispherical, 3-50 μm high by 50-70 μm wide. Spores brownish when mature, 6.0-8.5 μm×4.5-6.0 μm. Spore walls conspicuously marked by longitudinal striations.

EXAMPLE 142 Preparation of (S)-4-hydroxy- 1-octyne

A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example 141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]_(D) ²⁵ =+ 17±1.0° (C=0.77, ethyl acetate). This compound has the (S)-configuration.

EXAMPLES 143-148

The starting 1-alkyn-4-ols of Table 17 below are converted to the triphenylmethoxy substituted 1-alkynes by the method of Example 98.

                  TABLE 17                                                         ______________________________________                                                                 Product Triphenyl-                                              Starting 1-Alkyn-                                                                             methoxy Substituted                                    Example  4-ol of Example                                                                               1-Alkyne                                               ______________________________________                                         143      116            4-triphenylmethoxy-5-                                                          trans-nonen-1-yne                                      144      120            5-methyl-4-triphenyl-                                                          methoxy-1-octyne                                       145      121            5-methyl-4-triphenyl-                                                          methoxy-1-nonyne                                       146      124            4-triphenylmethoxy-5-                                                          trans-octene-1-yne                                     147      141            (R)-4-triphenylmeth-                                                           oxy-1-octyne                                           148      142            (S)-4-triphenylmeth-                                                           oxy-1-octyne                                            148a     124a          4-triphenylmethoxy-5-                                                          trans-decen-1-yne                                      ______________________________________                                    

EXAMPLES 149-154

The product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of Table 18 below are prepared from the starting triphenylmethoxy substituted 1-alkynes of the table by the procedure described in Example 107.

                  TABLE 18                                                         ______________________________________                                               Starting Tri-                                                                  phenylmeth-                                                                    oxy Substi-                                                              Ex-   tuted 1-Alkyn                                                                             Product Triphenylmethoxy Substituted                          ample of Example 1-Iodo-trans-1-alkene                                         ______________________________________                                         149   143        1-iodo-4-triphenylmethoxy-trans,trans-                                         1,5-nonadiene                                                 150   144        1-iodo-5-methyl-4-triphenylmethoxy-                                            trans-1-octene                                                151   145        1-iodo-5-methyl-4-triphenylmethoxy-                                            trans-1-nonene                                                152   146        1-iodo-4-triphenylmethoxy-trans,trans-                                         1,5-octadiene                                                 153   147        (R)-1-iodo-4-triphenylmethoxy-1-trans-                                         octene                                                        154   148        (S)-1-iodo-4-triphenylmethoxy-1-trans-                                         octene                                                         154a  148a      i-iodo-4-triphenylethoxy-trans, trans-                                         1,5-decadiene                                                 ______________________________________                                    

EXAMPLE 155 Preparation of ethyl-p-fluorophenoxy-acetate

To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25° C. to give 55 g (90%) of the subject product as colorless crystals, mp 32°-33° C.

EXAMPLE 156 Preparation of p-fluorophenoxy acetaldehyde

To a stirred solution of 1.98 g (10 mmoles) of ethyl-p-fluorophenoxy acetate (Example 155) in 15 ml of dry toluene, cooled to -78° C., under argon, is added, dropwise over 30 minutes, 8 ml of a 1.4 M solution of diisobutylaluminum hydride in toluene (11 mmoles). The mixture is stirred for 2 hours at -78° C., 1 ml of methanol is added, followed by 5 ml of water, dropwise. The gel formed is filtered through Celite and washed with 100 ml of ether, portionwise. The organic phase is separated, washed twice with 25 ml of a saturated brine solution, dried with magnesium sulfate, filtered, and evaporated. The oil obtained is distilled at 71°-73° C. (0.1 mm) to give 600 mg (45%) of the subject product as a colorless liquid.

EXAMPLE 157 Preparation of 3-hydroxy-4-p-flurorphenoxy-1-butyne

Acetylene gas, dried by passing through a trap containing sulfuric acid, is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes. To this acetylenic solution, is then added dropwise, with continued passage of acetylene, 3.5 ml of a 2.4 M solution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles) over 45 minutes. The mixture is stirred a further 15 minutes, and a solution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example 156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. This solution is stirred for 2 more hours, with passage of acetylene, poured into 50 ml of a saturated solution of ammonium chloride, extracted twice with 50 ml of ether, washed with 10 ml of ammonium chloride solution, dried with magnesium sulfate, filtered, and evaporated. The crude subject product is purified by sublimation at 75° C. (0.1 mm) for 5 hours to give 330 mg (48%) of white crystals, mp 46°-47° C.

EXAMPLE 158 Preparation of 4-p-fluorophenoxy- 3-trimethylsilyloxy-1-butyne

To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamide and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then porued into 150 ml of hexane and 100 ml of ice-water. The organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.

EXAMPLE 159 Preparation of 1-tri-n-butylstannyl-4-p-fluorophenoxy-3-trimethylsilyloxy-trans-1-butene

A mixture of 2.52 g (10 mmoles) of 3-trimethylsilyloxy-4-p-fluorophenoxy-1-butyne (Example 158), 2.91 g (10 mmoles) of tri-n-butyl-tin hydride, and 10 mg of azobisisobutyronitrile is heated, under an argon atmosphere, with stirring, for 2 hours at 140° C. After cooling to room temperature, the crude reaction mixture is fractionally distilled at 180°-185° C. (0.05 mm), to give 4.6 g (85%) of the subject product as a colorless liquid.

EXAMPLES 160-162

The product esters of Table 19 below are obtained by the procedure described in Example 155.

                  TABLE 19                                                         ______________________________________                                                 Starting Aryloxy                                                                               Product Aryloxy                                        Example Acid            Ethyl Ester                                            ______________________________________                                         160     m-chlorophenoxy-                                                                               ethyl-m-chlorophenoxy-                                         acetic acid     acetate                                                161     3,4-dichlorphe- ethyl-3,4-dichlorophe-                                         noxyacetic acid noxyacetate                                            162     phenoxyacetic acid                                                                             ethyl phenoxyacetate                                   ______________________________________                                    

EXAPLE 163 Preparation of ethyl-m-trifluoromethylphenoxy-acetate

A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotorary evaporator at 45° C. and at 85° C. (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1 M potassium carbonate, once with 100 ml of water, 100 ml of 0.01 M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75° C. (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.

EXAMPLES 164-166

The product esters of Table 20 are obtained by treating the starting phenols with ethyl bromoacetate by the procedure of Example 162.

                  TABLE 20                                                         ______________________________________                                         Example Starting Phenol                                                                               Product Ester                                           ______________________________________                                         164     p-bromophenol  ethyl p-bromophenoxy-                                                          acetate                                                 165     4-t-butylphenol                                                                               ethyl 4-t-butylphenoxy-                                                        acetate                                                 166     p-methoxyphenol                                                                               ethyl p-methoxyphenoxy-                                                        acetic acid                                             ______________________________________                                    

EXAMPLES 167-173

Following the procedure of Example 156, the starting esters of Table 21 are treated with diisobutylaluminum hydride to provide the product aldehydes of the table.

                  TABLE 21                                                         ______________________________________                                         Example  Starting Ester                                                                               Product Aldehyde                                        ______________________________________                                         167      163           m-trifluoromethylphenoxy                                                       acetaldehyde                                            168      164           p-bromophenoxy acetalde-                                                       hyde                                                    169      165           4-t-butylphenoxy acetal-                                                       dehyde                                                  170      166           p-methoxyphenoxy acetalde-                                                     hyde                                                    171      160           m-chlorophenoxy acetalde-                                                      hyde                                                    172      161           3,4-dichlorophenoxy acet-                                                      aldehyde                                                173      162           phenoxyacetaldehyde                                     ______________________________________                                    

EXAMPLES 174-180

Following the procedure of Example 156, treatment of the starting aldehyde of Table 22 with acetylene magnesium chloride provides the product alkynes of Table 22.

                  TABLE 22                                                         ______________________________________                                                   Starting                                                             Example   Aldehyde  Product Aryloxy Alkyne                                     ______________________________________                                         174       167       3-hydroxy-4-m-trifluoromethyl-                                                 phenoxy-1-butyne                                           175       168       3-hydroxy-4-p-bromophenoxy-1-                                                  butyne                                                     176       169       3-hydroxy-4-t-butylphenoxy-1-                                                  butyne                                                     177       170       3-hydroxy-4-p-methoxyphenoxy-                                                  1-butyne                                                   178       171       3-hydroxy-4-m-chlorophenoxy-                                                   1-butyne                                                   179       172       3-hydroxy-4-(3,4-dichlorophe-                                                  noxy)-1-butyne                                             180       173       3-hydroxy-4-phenoxy-1-butyne                                180a     a         3-hydroxy-5-phenyl-1-pentyne                                180b     b         3-hydroxy-5-(p-chlorophenyl)-                                                  1-pentyne                                                   180c     c         3-hydroxy-5-(p-methoxyphenyl)-                                                 1-pentyne                                                   180d     d         3-hydroxy-5-(m-trifluorometh-                                                  ylphenyl)-1-pentyne                                        ______________________________________                                          a hydrocinnamaldehyde.sup.1?                                                   b p-chlorohydrocinnamaldehyde.sup.1?                                           c p-methoxyhydrocinnamaldehyde.sup.1?                                          d m-trifluoromethylhydrocinnamaldehyde.sup.2?                                  .sup.1 Billman, et al., Synthetic Communications, 1, 127-131 (1971).           .sup.2 Lednicer, Journ. Med. Chem., 11, 1258 (1968).                     

EXAMPLES 181-186

Treatment of the starting alkynes of Table 23 by the procedure of Example 158 followed by treatment of the procedure of Example 159 provides the product (E) 1-tri-n-butyltin-1-alkenes of the table.

                  TABLE 23                                                         ______________________________________                                         Exam- Starting                                                                 ple   Alkyne   Product (E)-1-tri-n-butyltin-1-alkene                           ______________________________________                                         180   174      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                m-trifluoromethylphenoxy-1-butene                               181   175      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                p-bromophenoxy-1-butene                                         182   176      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                t-butylphenoxy-1-butene                                         183   177      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                p-methoxyphenoxy-1-butene                                       184   178      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                m-chlorophenoxy-1-butene                                        185   179      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-                                  3,4-dichlorophenoxy-1-butene                                    186   180      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                phenoxy-1-butene                                                186a  48       (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-                                   trimethylsilyloxy-(Z)-6-octadiene                               186b  180a     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                phenyl-1-pentene                                                186c  180b     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                (p-chlorophenyl)-1-pentene                                      186d  180c     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                (p-methoxyphenyl)-1-pentene                                     186e  180d     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                (m-trifluoromethylphenyl)-1-pentene                             ______________________________________                                    

EXAMPLE 187 Preparation of 1-chloro-1-octen-3-one

This compound is prepared according to the procedure of Price and Pappalardo [C. C. Price and J. A. Pappalardo, Org. Syn., 32, 27 (1952)] from hexanoyl chloride, acetylene, and aluminum chloride in 94% yield, bp 51°-52° C. (0.1 mm); λ max 1680, 1595, 941 cm⁻¹.

EXAMPLE 188 Preparation of 1-iodo-1-octen-3-one

A mixture of 25 g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187) and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone is stirred at the reflux temperature for 18 hours. The cooled mixture is filtered and the mother liquor taken to dryness. The residual oil is dissolved in benzene and the solution is washed with 5% sodium thiosulfate solution, saturated sodium chloride solution, dried and taken to dryness. The residual oil is crystallized from hexane to give 26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm⁻¹.

EXAMPLE 189 Preparation of 3-hydroxy-1-iodo-3-methyl-1-octene

To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2.89, 3.23, 6.24 and 10.5.

EXAMPLE 190 Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-octene

To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1-octene (Example 184) and 7.4 g of imidazole in 45 ml of dry dimethylformamide is added dropwise 5.98 g of trimethylsilylchloride at 0° C. under argon atmosphere. After stirring at 0° C. for an additional 15 minutes, the solution is stirred at ambient temperature for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of oil. Distillation affords 13.4 g of clear oil; bp 65° C. (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.

EXAMPLE 190a Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-decene

Treatment of octanoylchloride by the procedures of Example 187 followed by treatment of the resulting 1-chloro-1-decen-3-one by the procedure of Example 188 followed by treatment according to Examples 189 and 190 is productive of the named compound.

EXAMPLE 191 Preparation of 4-trimethylsiloxy-1-octyne

To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10, 289 (1975)], and 240 g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine dried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, bp 38° C. (0.2 mm).

EXAMPLE 192 Preparation of 1-iodo-4-trimethylsiloxy-trans-1-octene

To a stirred solution of 0.20 moles of freshly prepared bis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5°C is added dropwise a solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30 ml of tetrahydrofuran. The resulting mixture is stirred at ambient temperature for several hours, cooled in an ice bath, and treated with 53 g of trimethylamine oxide. The mixture is stirred several hours at 25°- C. C. and then poured into 2 liters of 15% sodium hydroxide. The resulting mixture is treated immediately with a solution of 140 g of iodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase is separated and the aqueous phase is extracted with ether. The combined organic layers are washed with water, sodium thiosulfate solution, and brine; dried over magnesium sulfate; and concentrated to give an oil, pmr spectrum (CDCl₃): 6.2 (d, ICH═) and 6.7 (quintuplet, ═CH--).

EXAMPLE 193 Preparation of 4 -hydroxy-1-iodo-trans-1-octene

A 23 g portion of 1-iodo-4-trimethylsilyloxy-1-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. Concentration provides the named product.

EXAMPLE 194 Preparation of 4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 456 mg of 4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0 m of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during 3 minutes. The mixture is stirred at room temperature for 22 hours and partitioned with a mixture of cold hexane and water. The hexane layer is washed repeatedly with water and then brine, dried over magnesium sulfate, and concentrated to give an oil, pmr spectrum (CDCl₃): 0.13 (s, trimethylsiloxy group) and 2.32 (d, ═CHCH₂).

EXAMPLE 195 Preparation of n-butyl cyclopropyl ketone

To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice: 4 N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, bp 102°-104° C. (80 mm), pmr spectrum (CDCl₃): δ 2.55 (triplet, --CH₂ CO--).

EXAMPLE 196 Preparation of 4-cyclopropyl-4-hydroxy-1-octyne

To a stirred, refluxing suspension of amalgum prepared from 6.2 g of magnesium and 50 mg of mercuric chloride suspended in 60 ml of ether is added a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone (Example 189) and 29.8 g of propargyl bromide in 65 ml of ether during 60 minutes. After reaction at reflux temperature for an additional 30 minutes, the mixture is cooled to 0° C. and treated with 35 ml of saturated ammonium chloride. The mixture is diluted with ether and filtered through Celite. The filtrate is washed with brine, dried over potassium carbonate, and concentrated. The residue is distilled to provide a liquid, δ 0.43 (cyclopropyl hydrogens), 2.07 (triplet, HC.tbd.C), and 2.44 (doublet, C.tbd.CCH₂).

EXAMPLE 197 Preparation of 4-cyclopropyl-4-trimethylsiloxy-1-octyne

To a stirred solution of 27.8 g of 4-cyclopropyl-4-hydroxy-1-octyne (Example 190) and 33.3 g of imidazole in 130 ml of dimethylformamide at 5° C. is added 24 ml of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, pmr spectrum (CDCl₃): δ 0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC.tbd.C), and 2.45 (doublet, C.tbd.CH₂).

EXAMPLE 198 Preparation of 4-cyclopropyl-4-trimethylsiloxy-1-(tri-n-butylstannyl)-trans-1-octene

A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne (Example 191), 28 ml of tri-n-butyltin hydride, and 50 mg of azobisisobutyronitrile under nitrogen is heated to 85° C. After the resulting exothermic reaction subsides the mixture is heated at 130° C. for one hour. The crude product is evaporatively distilled to give a liquid, pmr spectrum (CDCl₃): δ 0.10 (trimethylsiloxy group), 2.33 (doublet, ═CHCH₂), and 6.02 (vinyl hydrogens).

EXAMPLES 199-204

Treatment of the starting carboxylic acids of Table 24 with the appropriate alkyllithium by the method of Example 190 provides the product ketones of the table.

                                      TABLE 24                                     __________________________________________________________________________          Starting                                                                  Example                                                                             Carboxylic Acid                                                                         Alkyl Lithium                                                                          Product Ketone                                           __________________________________________________________________________     199  cyclopropane                                                                            n-hexyllithium                                                                         n-hexylcyclopropyl ketone                                     carboxylic acid                                                           200  cyclopropane                                                                            n-propyllithium                                                                        n-propylcyclopropyl ketone                                    carboxylic acid                                                           201  acrylic acid                                                                            n-hexyllithium                                                                         n-hexylvinyl ketone                                      202  acrylic acid                                                                            n-propyllithium                                                                        n-propylvinyl ketone                                     203  crotonic acid                                                                           n-butyllithium                                                                         n-butyl-1-propenyl ketone                                204  crotonic acid                                                                           n-hexyllithium                                                                         n-hexyl-1-propenyl-ketone                                 204a                                                                               acrylic acid                                                                            n-butyllithium                                                                         n-butylvinyl ketone                                      __________________________________________________________________________

EXAMPLES 205-210e chlorotrimethylsilane

Treatment of the starting ketones of Table 25 with propargymagnesium bromide by the procedure of Example 190 followed by treatment with chororimethylsilane by the procedure of Example 191 followed by treatment with tri-n-butyltin hydride by the method of Example 192 is productive of the vinylstannyl derivatives of the table.

                  TABLE 25                                                         ______________________________________                                                Starting                                                                Example                                                                               Ketone     Product Vinylstannyl Derivative                              ______________________________________                                         205    199        (E)4-trimethylsilyloxy-4-cyclopropyl-1-                                        tri-n-butylstannyldecene                                     206    200        (E)4-trimethylsilyloxy-4-cyclopropyl-1-                                        tri-n-butylstannylheptene                                    207    201        (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                        butylstannyldecene                                           208    202        (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                        butylstannylheptene                                          209    203        (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                                       tri-n-butylstannyloctene                                     210    204        (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                                       tri-n-butylstannyldecene                                     210a   204a       (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                        butylstannyloctene                                           210b   2-hexanone (E)-4-trimethylsilyloxy-4-methyl-1-tri-n-                                      butylstannyloctene                                           210c   3-heptanone                                                                               (E)-4-trimethylsilyloxy-4-ethyl-1-tri-n-                                       butylstannyloctene                                           210d   3-octanone (E)-4-trimethylsilyloxy-4-ethyl-1-tri-n-                                       butylstannylnonene                                           210e   3-hexanone (E)-4-trimethylsilyloxy-4-ethyl-1-tri-n-                                       butylstannylheptene                                          ______________________________________                                    

EXAMPLE 211 Preparation of trans-1-Hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane

A mixture of 88 g of cyclopentene oxide, 150.7 g of 3-trifluoromethylphenol, 5.0 g of sodium hydroxide in 30 ml of water and 4.0 g of methyltricaprylyl ammonium chloride is stirred at 70°-80° C. for 51 hours and at 25° C. for 96 hours. The mixture is then diluted with methylene chloride and poured into water. The organic layer is washed with dilute sodium hydroxide solution and water. The solution is dried over magnesium sulfate. The solvent is removed giving 221.5 g of a liquid which is distilled (bp 110°-113° C. 0.8 mm) giving trans-1-hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane.

EXAMPLE 212

In the manner described above in Example 211 from 4-fluorophenol and cyclopentane epoxide is prepared trans-1-hydroxy-2-(4-fluoro)phenoxycyclopentane.

EXAMPLE 213

In the manner described above in Example 211 from 3-chlorophenol and cyclopentane epoxide is prepared trans-1-hydroxy-2-(3-chloro)phenoxycyclopentane.

EXAMPLE 214 Preparation of 2-(3-Trifluoromethylphenoxy)cyclopentanone

To a suspension of 327.43 g of pyridinium chlorochromate in one liter of methylene chloride is added 220 g of trans-1-hydroxy-2-(3-trifluoromethylphenoxy)cyclopentane in 500 ml of methylene chloride. The mixture is stirred for 2 hours 15 minutes. Another 50 g of the oxidizing agent is added and the mixture is stirred for 41/2 hours. The mixture is diluted with ether and decanted from a black residue which is washed with more ether. The combined solutions are filtered through silica gel. The solvent is removed. The residue is dissolved in ether and again filtered through silica-gel. The solvent is removed and the residue is distilled (bp 113°-116° C., 1.5 mm) to give 188 g of 2-(3-trifluoromethylphenoxy)cyclopentanone.

EXAMPLE 215

In the manner described above for Example 214 is prepared from the product of Example 212; 2-(4-(fluorophenoxy)cyclopentanone.

EXAMPLE 216

In the manner described above for Example 214 is prepared from the product of Example 213; 2-(3-chlorophenoxy)cyclopentanone.

EXAMPLE 217 Preparation of 1R,2S(and 1S,2R)-1-Ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane

Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as a solution of 2.4 M n-butyl magnesium chloride (92 ml) is added dropwise with stirring over a 2 hour period. To the resulting solution of acetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in 50 ml of tetrahydrofuran dropwise over 15 minutes. The solution is stirred for 30 minutes and then is poured into an ice cold solution of saturated ammonium chloride. The mixture is acidified to pH 5 and extracted with ether. The ether solution is washed with brine and dried over magnesium chloride. The ether is removed and the residue is distilled giving 14.8 g of a colorless liquid. This is chromatographed on a dry column of silica-gel eluting with benzene-ethyl acetate (19:1) to separate isomers giving 1R,2S(and 1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane.

EXAMPLE 218 Preparation of 1-propargyl-1-hydroxycyclohexane

A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1 of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargyl bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane.

EXAMPLES 219-238

In the manner of Examples 217 and 218 described above the following acetylenic alcohols listed in Table 26 were prepared from the acetylenic Grignard reagent and ketone specified.

                                      TABLE 26                                     __________________________________________________________________________     Example                                                                             Grignard Reagent                                                                         Ketone      Acetylenic Alcohol                                  __________________________________________________________________________     219  acetylene magne-                                                                         cyclohexanone                                                                              1-ethynyl-1-hydroxycyclohexane                           sium chloride                                                             220  acetylene magne-                                                                         cyclopentanone                                                                             1-ethynyl-1-hydroxycyclopentane                          sium chloride                                                             221  acetylene magne-                                                                         cycloheptanone                                                                             1-ethynyl-1-hydroxycycloheptane                          sium chloride                                                             222  acetylene magne-                                                                         3-propylcyclopentanone                                                                     1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                  sium chloride         3-propylcyclopentane                                223  acetylene magne-                                                                         3-propylcyclopentanone                                                                     1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                  sium chloride         3-proylcyclopentane                                 224  acetylene magne-                                                                         2-butylcyclohexanone                                                                       1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride         2-butylcyclohexane                                  225  acetylene magne-                                                                         2-butylcyclohexanone                                                                       1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride         2-butylcyclohexane                                  226  acetylene magne-                                                                         2-(3-trifluoro-                                                                            1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopen-                              cyclopentanone                                                                             tane                                                227  acetylene magne-                                                                         2-(3-trifluoro-                                                                            1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopentane                           cyclopentanone                                                  228  acetylene magne-                                                                         2-(4-fluorophen-                                                                           1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            oxy)cyclopentanone                                                                         2-(4-fluorophenoxy)cyclopentane                     229  acetylene magne-                                                                         2-(4-fluorophen-                                                                           1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            oxy)cyclopentanone                                                                         2-(4-fluorophenoxy)cyclopentane                     230  acetylene magne-                                                                         2-(3-chlorophenoxy)-                                                                       1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            cyclopentanone                                                                             2-(3-chlorophenoxy)cyclopentane                     231  acetylene magne-                                                                         2-(3-chlorophenoxy)-                                                                       1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            cyclopentanone                                                                             2-(3-chlorophenoxy)cyclopentane                     232  acetylene magne-                                                                         3-methylcyclohexa-                                                                         1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            none        3-methylcyclohexane                                 234  acetylene magne-                                                                         3-methylcyclohexa-                                                                         1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                            none        3-methylcyclohexane                                 235  propargyl magne-                                                                         2-butylcyclopenta-                                                                         1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                sium bromide                                                                             none        2-butylcyclopentane                                 236  propargyl magne-                                                                         2-butylcyclopenta-                                                                         1R,2R-(and 1S,2S-) 1-propargyl-1-hydroxy-                sium bromide                                                                             none        2-butylcyclopentane                                 237  propargyl magne-                                                                         2-(3-trifluoro-                                                                            1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                sium bromide                                                                             methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopentane                           cyclopentanone                                                  238  propargyl magne-                                                                         2-(3-trifluoro-                                                                            1R,2R-(and 1S,2S-) 1-propargyl-1-hydroxy-                sium bromide                                                                             methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopentane                           cyclopentanone                                                  __________________________________________________________________________

EXAMPLE 239 Preparation of 1R,2S(and 1S,2R)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a solution of 29.4 g of 1R,2S(and 1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazole in 180 ml of dimethylformamide is added at 0° C. with stirring 24.1 g of trimethylsilylchloride. The mixture is stirred for 3 hours. The mixture is poured into 700 ml of hexane and washed twice with water and once with brine. The ether solution is dried over magnesium sulfate. The solvent is removed and the residue is distilled (bp 64°-72° C., 0.6 mm) to give 35.8 g of 1R,2S(and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 240 Preparation of 1R,2R(and 1S,2S)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 45.0 g of 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 46.2 g of imidazole in 255 ml of dimethylformamide at 0° C. under nitrogen is added 36.9 g of trimethylsilylchloride. The mixture is stirred at room temperature for 3 hours and then poured into 700 ml of hexane. Water is added, the organic layer is separated and the water layer is extracted with hexane. The combined hexane solutions are washed twice with water and dried over magnesium sulfate. The solvent is removed and the residue is distilled giving the product as 53 g of a colorless oil.

EXAMPLE 241 Preparation of 1-Ethynyl-1-trimethylsilyloxycyclohexane

A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, diluted with water and extracted with hexane. The hexane layers are washed several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.

EXAMPLE 242 Preparation of 1-Propargyl-1-trimethylsilyloxycyclohexane

To a stirred solution of 55.4 g of 1-(2-propyn-1-yl)cyclohexanol [H. Gutmann, et al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazole in 240 ml of DMF at 10° C. initially is added 56 ml of chlorodimethylsilane during 10 minutes. The cloudy yellow solution is stirred at room temperature for 26 hours. The resulting mixture is partitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C. The hexane phase is washed successively with 6×200 ml of cold water and 200 ml of brine. The extract is dried over magnesium sulfate, filtered, and evaporated to give 85 g of colorless liquid, i.r. (film):1240 and 830 cm⁻¹ (trimethylsilyloxy group).

EXAMPLE 243 Preparation of 1R,2S(and 1S,2R)-1-(trans-2-Iodovinyl)-1 -trimethylsilyloxy-2-butylcyclopentane

To a mixture of 9.2 g of sodium borohydride and 45.8 g of 2-methyl-2-butene in 350 ml of dry tetrahydrofuran at 0° C. with stirring under nitrogen is added, over 20 minutes, 41.1 ml of boron trifluoride etherate. After 3 hours, to this resulting solution of diisomaylborane is added 38.8 g of 1R,2S(and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butycyclopentane in 40 ml of tetrahydrofuran in 20 minutes. The mixture is stirred 2 hours and then stored at -20° C. overnight. The mixture is allowed to warm to 0° C. and at 0° C. 85 g of dry trimethylamineoxide is added portionwise over 20 minutes. After stirring at 25° C. for one hour, the mixture is filtered through diatomaceous earth. The filtrate is poured simultaneously with a solution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred, cold solution of 430 g of sodium hydroxide in 1900 ml of water. After stirring for 30 minutes, the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed twice with a saturated solution of sodium thiosulfate and once with brine. The solution is dried over magnesium sulfate, the solvent is removed and the residue is dissolved in hexane. The hexane solution is filtered through diatomaceous earth and silica gel. The hexane is removed and the residue is purified by dry column chromatography on silica gel eluting with hexane: 45.35 g of 1R,2S(and 1S,2R)-1-(trans-2-iodovinyl)1-trimethylsilyloxy-2-butylcyclopentane is obtained.

EXAMPLE 244 Preparation of 1R,2R(and 1S,2S)-1-(trans-2-Iodovinyl)-1 -trimethylsilyloxy-2-butylcyclopentane

To a mixture of 12.22 g of sodium borohydride and 60.82 g of 2-methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0° C., is added 54.6 ml of boron trifluoride ehterate, dropwise over a 20 minute period. The solution is stirred at 0° C. for 2 hours and then at room temperature for 30 minutes. This solution is cooled to 0° C. and 55.5 g of 1R,2R(and 1S,2S)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 50 ml of tetrahydrofuran is added. The mixture is allowed to stand in a cold room overnight. To this mixture at 0° C. is added with stirring 112.8 g of trimethylamine oxide over a 20 minute period. The mixture is stirred at room temperature for 90 minutes and then filtered. To the filtrate is added simultaneously a solution of 565 g of sodium hydroxide in 2000 ml of water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran. The mixture is stirred 30 minutes, the organic layer is separated and the aqueous layer is extracted with ether. The combined organic solutions are washed with saturated sodium thiosulfate solution and with saturated sodium chloride solution. The solution is dried with magnesium sulfate and filtered through a pad of silica gel. The solution is removed giving an orange liquid which is chromatographed on a dry column of silica gel giving 59.5 g of the product as a yellow liquid.

EXAMPLE 245 Preparation of 1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp 150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLES 246-265

Using the procedure outlined above for Examples 239-242, the acetylenic alcohols listed in Table 27 are converted to their corresponding acetylenic trimethylsilyloxy derivative these in turn using the procedure outlined above for Examples 243 and 244, were converted to their corresponding trans-2-iodovinyl derivatives or using the procedure outlined above for Example 245, were converted to their corresponding trans-2-tri-n-butylstannyl derivatives (Table 27).

                                      TABLE 27                                     __________________________________________________________________________     Example                                                                             Acetylene of Example                                                                      Method of Example                                                                        Vinyl Iodide or Vinyl Tin Compound                   __________________________________________________________________________     246  219        244       1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                     cyclohexane                                          247  220        244       1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                     cyclopentane                                         248  221        245       1-(trans-2-tri-n-butylstannylvinyl)-1-tri-                                     methylsilyloxycycloheptane                           249  222        244       1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-propylcyclopentane               250  223        244       1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-propylcyclopentane               251  217        244       1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-butylcyclopentane                252  224        244       1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-butylcyclohexane                 253  225        244       1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-butylcyclohexane                 254  226        245       1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl-2-trimethylsilyloxy-2-(3-                                         trifluoromethylphenoxy)cyclopentane                  255  227        245       1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-tri-                                    fluoromethylphenoxy)cyclopentane                     256  228        244       1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-                                      trimethylsilyloxy-2-(4-fluorophenoxy)-                                         cyclopentane                                         257  229        244       1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-                                      1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                       cyclopentane                                         258  230        245       1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-                                        chlorophenoxy)cyclopentane                           259  231        245       1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-                                        chlorophenoxy)cyclopentane                           260  232        244       1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-methylcyclohexane                261  234        244       1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-methylcyclohexane                262  235        245       1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       butylcyclopentane                                    263  236        245       1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       butylcyclopentane                                    264  237        245       1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       (3-trifluoromethylphenoxy)cyclopentane               265  238        245       1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       (3-trifluoromethylphenoxy)cyclopentane               __________________________________________________________________________

EXAMPLE 266 Preparation of trimethylsilyl-2-trimethylsilyloxy acetate

To a solution of 15 g (0.197 mol) of glycolic acid in 50 ml of dry pyridine is poured 32.3 g (0.2 mol) of 1,1,1,3,3,3-hexamethyldisilazine. After stirring 15 minutes, 10.86 g (0.1 mol) of trimethylsilyl chloride is added dropwise. The mixture is stirred for one hour and then filtered from a white solid which is washed with petrolium ether. The filtrate and washings are concentrated at reduced pressure at 30° C. The residue is distilled (85°-86°, 15 minutes) to give 38 g of the title compound.

EXAMPLE 267 Preparation of tris-trimethylsilyloxyethylene

To a solution of 50.98 g (0.316 mol) of 1,1,1,3,3,3-hexamethyldisilazine in 250 ml of tetrahydrofuran is added with stirring under argon at 0° C. dropwise 133.3 ml (0.32 mol) of 2.4 M n-butyl lithium in hexane. After addition is completed the solution is maintained at 45° C. for 30 minutes. The solution is cooled to -78° and 58.7 g of trimethylsilyl-2 -trimethylsilyloxy acetate (Example 266) is added dropwise. After stirring 30 minutes, 43.2 g (0.4 mol) of trimethylsilylchloride is added over 10 minutes. The solution is allowed to warm to room temperature over 30 minutes. The solvent is removed at reduced pressure. The residue is mixed with an equal volume of petrolium ether and filtered from the suspended lithium chloride. The solvent is removed and the residue is distilled (70°-75° C., 1.4 minute) to give 64.65 g of the title compound.

EXAMPLE 268 Preparation of 2-[6-(chloroformyl)hexyl]cyclopent-2-en-1-one

To a suspension of 1.94 g (0.08 mol) of sodium hydri in 100 ml of tetrahydrofuran is added with stirring under argo dropwise a solution of 17 g (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to give 16.0 g of the title compound.

EXAMPLE 269 Preparation of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one

A mixture of 6.3 g of 2-[6-(chloroformyl)hexyl]-cyclopent-2-en-1-one (Example 268) and 16 g of tris-trimethylsilyloxyethylene (Example 267) are stirred at 90° to 100° C. under argon for one hour. To this mixture is added 25 ml of dioxane and 10 ml of 0.6 N hydrochloric acid. The mixture is heated at 80° C. for 30 minutes. The mixture is poured into brine and extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether containing 2% acetic acid to give 1.7 g of the title compound (R_(f) =0.45).

EXAMPLE 270 Preparation of 2-(6-carbodimethyl-t-butylsilyloxyhex-2-cis-en-yl)-4-dimethyl-t-butylsilyloxy-cyclopent-2-en-1-one

To 5.0 g of 2-(6-carboxyhex-2-enyl)-4-hydroxycyclopent-2-en-1-one and 7.5 g of imidazole in 24 ml of dimethylformamide is added 10.2 g of dimethyl-t-butylsilylchloride. The mixture is maintained at 37° C. for 4 hours. The mixture is poured into ice water and extracted with hexane. The hexane solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. Toluene is added and removed. The residue is distilled in a Kugelrohr apparatus (165° C., 0.5-0.1 mm) to give 4.56 g of the title compound.

EXAMPLE 271 Preparation of 1-(6-carboxyhex-2-cis-enyl)-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one

A solution of 1-(6-carbodimethyl-t-butylsilyloxyhex-2-cis-enyl)-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one (Example 270) in 40 ml of acetic acid-- tetrahydrofuran--water (4:2:1) is stirred at room temperature for 1.5 hour. The solvents are removed at reduced pressure at 40° C. The residue is dissolved in ether. The ether solution is washed with water, brine, and dried over magnesium sulfate. The solvent is removed. Toluene is added and removed to give 3.1 g of the title compound.

EXAMPLE 272 Preparation of 1-[6-(chloroformyl)hex-2-cis-enyl]-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one

To 59.66 g of 1-(6-carboxyhex-2-cis-enyl)-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one (Example 271) in 300 ml of tetrahydrofuran containing 0.5 ml of dimethylformamide at 0° C. under argon with stirring is added over 20 minutes 29.2 m of oxalyl chloride in 40 ml of tetrahydrofuran. After 1.5 hour, the solvent is removed at reduced pressure at 35° C. The residue is dissolved in petrolium ether and filtered through Celite. The solvent is removed to give 59.3 g of the title compound.

EXAMPLE 273 Preparation of 1-(8-hydroxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one

A mixture of 59.3 g of 1- [6-(chloroformyl)hex-2-cis-enyl]-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one (Example 272) and 101.5 g of tris-trimethylsilyloxyethylene (Example 267) is heated under argon at 90°-95° C. for 3 hours 10 minutes. The reaction mixture is poured into a mixture of 300 ml of tetrahydrofuran and 140 ml of 0.6 N hydrochloric acid and the resulting mixture is stirred at 70° C. for 2.5 hours. The mixture is poured in brine and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and dried of magnesium sulfate. The solvent is removed and the residue is chromatographed of a dry column of silica gel eluting with ethyl acetate. The product bond (R_(f) ≈0.4) is extracted to give 6.45 g of the title compound.

EXAMPLE 274 Preparation of 5-bromopentanoylchloride

To a solution of 97 g of 5-bromopentanoic acid in 240 ml of methylene chloride containing 1 ml of dimethylformamide is added dropwise 76.2 g of oxalyl chloride. The mixture is stirred one hour at room temperature and 30 minutes at 50° C. The solvent is removed and the residue is distilled twice (75° C., 0.6 minute) to give 88.2 g of the title compound.

EXAMPLE 275 Preparation of 6-bromo-1-hydroxy-2-hexanone

To 191.4 g of tris-trimethylsilyloxyethylene (Example 267) containing 15 drops of stannic tetrachloride under argon with stirring at 10° C. is added 87 g of 5-bromopentanoyl chloride (Example 274) dropwise. After one-half of the acid chloride is added, the mixture is stirred until an exotherm ensues. The remaining acid chloride is added dropwise maintaining the reaction exotherm at 65° C. The mixture is then stirred for 2.5 hours. The mixture is slowly poured into a stirred mixture of 100 ml of 0.6 N hydrochloric acid and 200 ml of tetrahydrofuran. The mixture is stirred for 30 minutes and poured into brine. The mixture is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. The residue is mixed with petroleum ether and cooled in dry-ice-acetone to induce crystallization. The petrolium ether is decanted and the solid is dried at reduced pressure to give 64.72 g of the title compound.

EXAMPLE 276 Preparation of 6-bromo-1-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal

A mixture of 84 g of 6-bromo-1-hydroxy-2-hexanone (Example 275), 240 ml of ethylene glycol, and 1.7 g of p-toluenesulfonic acid is refluxed in 1800 ml of toluene using a Dean-Stark trap for 1 hour 45 minutes. The mixture is cooled to room temperature and washed with saturated sodium bicarbonate, water, and brine. The solvent is removed giving 75.17 g of a yellow oil. To a 27.36 g portion of this material and 16.2 g of imidazole in 57 ml of dimethylformamide at 0° with stirring is added 20.55 g of dimethyl-t-butylchlorosilane. The mixture is stirred at room temperature for 1.5 hour and then poured into water. The mixture is extracted with petrolium ether. The organic phase is washed with dilute hydrochloric acid, saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is distilled in a Klugrohr apparatus (0.5-0.2 mm, 100°-110° C.) to give 35.25 of the title compound.

EXAMPLE 277 Preparation of 1-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal 6-triphenylphosphonium bromide

A mixture of 35.25 g of 6-bromo-1-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal (Example 276) and 26.2 g of triphenylphosphine in 68 ml of acetonitrile is refluxed 90 hours. The acetonitrile is removed at reduced pressure. The residue is washed three times with ether and dried at reduced pressure to give 53.8 g of the title compound.

EXAMPLE 278 Preparation of 2,5-dihydro-2,5-dimethoxy-2-(9-dimethyl-t-butylsilyloxy-8-oxonon-3-cis-enyl)furan

A suspension of 2.3 g (0.096 mol) of oil free sodium hydride is stirred under argon at 65° C. in 75 ml of dimethylsulfoxide. After gas evolution ceased (1 hour), at 0° C. is added 53.8 g (0.086 mol) of 1-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal 6-triphenylphosphonium bromide (Example 277) in 160 ml of dimethylsulfoxide. After stirring 15 minutes at room temperature, 16.3 g (0.087 mol) of 2,5-dihydro-2,5-dimethoxy-2-(3'-oxopropyl)furan [U.S. Pat. No. 3,952,033] in 40 ml of dimethylsulfoxide is added. After stirring one hour at room temperature, the solvent is removed at reduced pressure at 55° C. The solid residue is extracted with an ether-petrolium ether mixture. The solution is washed with water, saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and petrolium ether is added. After standing 30 minutes, the triphenylphosphine oxide is removed by filtration. The solvent is removed and the residue is chromatographed on a dry column of florisil eluting first with hexane and then with hexane-ether 5:1 to give 13.2 g of the title compound.

EXAMPLE 279 Preparation of 2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one, 7-ethylene ketal

A mixture of 66.08 g of 2,5-dihydro-2,5-dimethoxy-2-(9-dimethyl-t-butylsilyloxy-8-oxonon-3-cis-enyl)furan (Example 228), 26.4 g of sodium dihydrogen phosphate, 5.2 g of sodium acetate and 0.5 g of hydroquinone in 1320 ml of dioxane and 660 ml of water is stirred at reflux under argon for 22 hours. The mixture is cooled to room temperature, saturated with sodium chloride, and the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed with brine and dried over magnesium sulfate. The solvent is removed to give 57.5 g of an oil. To this is added 300 ml of ether, 300 ml of petrolium ether and 22 g of anhydrous chloral. The solution is stirred under argon and 23 g of triethylamine is added. After 1 hour 40 minutes, the solution is washed with water, dilute hydrochloric acid, saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ethylacetate-hexane 1:1 to give 14.55 g of the title compound (R_(f) =0.4)

EXAMPLE 280 Preparation of 2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4trimethylsilyloxycyclopent-2-en-1-one, 7-ethylene keta

A mixture of 14.5 g (0.0367 mol) of 2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one,7-ethylene ketal (Example 279) and 3.34 g (0.04 mol) of imidazole in 30 ml of dimethylformamide is stirred as 4.98 g (0.046 mol) of trimethylsilylchloride is added. After one hour, the mixture is poured into water and extracted with hexane. The hexane solution is washed with water, saturated sodium bicarbonate, and dried over magnesium sulfate. The solution is filtered through a pad of silica gel. The solvent is removed and the residue is dried at reduced pressure to give 12.5 g of the title compound.

EXAMPLE281 Preparation of 2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-cis-enyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-one

A mixture of 2-(8-hydroxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one (Example 273), 14 ml of 2-methoxy propene, and 0.23 g of ammonium nitrate in 35 ml of benzene is added 7 ml of dimethoxypropane. P-toluenesulfonic acid is added in very small portions until TLC indicates the reaction is initiated. The mixture is stirred 1.5 hour at room temperature, 40° C. for 15 minutes, and another 30 minutes at room temperature. To the stirred solution is added 50 g of crushed 4A molecular sieve. After 15 minutes, the solution is filtered washed with saturated sodium bicarbonate, and dried over sodium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether-hexane 1:1. The product bond (R_(f) ≈0.5) is extracted to give 3.44 g of the title compound.

EXAMPLE 282 Preparation of 2-(8-hydroxy-7-oxo-octyl)cyclopent- 2-en-1-one,7-ethylene ketal

A solution of 5.5 g of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one (Example 269), 25 ml of ethylene glycol, and 0.1 g of p-toluenesulfonic acid in 200 ml of toluene is refluxed for 40 minutes using a Dean-Stark trap. THe solution is poured into saturated sodium bicarbonate. The mixture is extracted with benzene. The organic solution is washed three times with water and dried over magnesium sulfate. The solvent is removed to give 6.0 g of the title compound.

EXAMPLE 283 Preparation of 2-(8-trimethylsilyloxy-7-oxo-octyl)cyclopent-2-en-1-one, 7-ethylene ketal

To a solution of 2.2 g of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one,7-ethylene ketal (Example 232) in 20 ml of pyridine is added 4.6 ml of 1,1,1,3,3,3-hexamethyldisilazine and, dropwise, 2.3 ml of trimethylsilylchloride. After 15 minutes, the excess reagents and solvent is removed at reduced pressure. The residue is taken up in ether and filtered through a short pad of silica gel. The solvent is removed. Toluene is added and removed. The residue is dried at reduced pressure to give 2.77 g of the title compound.

EXAMPLE 284-294

By the sequence of reactions described hereinabove for Examples 268 and 269 or 270 to 273 and the protection reaction described hereinabove in Example 281, the protected cyclopent-2-en-1-ones listed in Table 28 hereinbelow are prepared from the indicated carboxylic acids.

                                      TABLE 28                                     __________________________________________________________________________     Example                                                                             Carboxylic acid                                                                               Protected cyclopent-2-en-1-one                             __________________________________________________________________________     284  2-(6-carboxyhexyl)cyclopent-                                                                  2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                2-en-1-one     hexylcyclopent-2-en-1-one                                  285  2-(5-carboxypentyl)cyclopent-                                                                 2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxoln-4-yl)-                 2-en-1-one     pentylcyclopent-2-en-1-one                                 286  2-(7-carboxyheptyl)cyclopent-                                                                 2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                2-en-1-one     heptylcyclopent-2-en-1-one                                 287  2-(6-carboxyhex-2-cis-enyl)-                                                                  2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                cyclopent-2-en-1-one                                                                          hex-2-cis-enyl]cyclopent-2-en-1-one                        288  2-(5-carboxypent-2-cis-enyl)-                                                                 2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                cyclopent-2-en-1-one                                                                          pent-2-cis-enyl]cyclopent-2-en-1-one                       289  2-(7-carboxyhept-2-cis-enyl)-                                                                 2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                cyclopent-2-en-1-one                                                                          hept-2-cis-enyl]cyclopent-2-en-1-one                       290  2-(5-carboxypent-2-cis-enyl)-                                                                 2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                4-hydroxycyclopent-2-en-1-                                                                    pent-2-cis-enyl]4-(2-methoxypropyl-2-oxy)cyclo-                 one            pent-2-en-1-one                                            291  2-(7-carboxyhept-2-cis-enyl)-                                                                 2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                4-hydroxycyclopent-2-en-1-                                                                    hept-2-cis-enyl]4-(2-methoxypropyl-2-oxy)cyclo-                 one            pent-2-en-1-one                                            292  2-(6-carboxyhexyl)-4-hydroxy-                                                                 2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                cyclopent-2-en-1-one                                                                          hexyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-                              one                                                        293  2-(5-carboxypentyl)-4-hydroxy-                                                                2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                cyclopent-2-en-1-one                                                                          pentyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-                               1-one                                                      294  2-(7-carboxyheptyl)-4-hydroxy-                                                                2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                cyclopent-2-en-1-one                                                                          heptyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-                               1-one                                                      295  2-(6-carboxyhex-2-cis-enyl)-                                                                  2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                4(R)-hydroxycyclopent-2-en-                                                                   hex-2-cis-enyl]-4(R)-(2-methoxypropyl-2-oxy)-cyclo-             1-one          pent-2-en-1-one                                            296  2-(6-carboxyhexyl)-4(R)-hy-                                                                   2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                droxycyclopent-2-en-1-one                                                                     hexyl]-4(R)-(2-methoxypropyl-2-oxy)cyclopent-2-en-                             1-one                                                      __________________________________________________________________________

EXAMPLES 297-298

By the sequence of reaction given hereinabove in the Examples 274 to 280, the protected cyclopent-2-en-1-ones of Table 29 are prepared from indicated Bromocarboxylic acid.

                                      TABLE 29                                     __________________________________________________________________________     Example                                                                             Bromo-carboxylic acid                                                                       Protected Cyclopent-2-en-1-one                               __________________________________________________________________________     297  4-bromobutanoyl-chloride                                                                    1-(7-dimethyl-t-butylsilyloxy-6-oxohept-2-                                     cis-enyl)-4-trimethylsilyloxycyclopent-2-en-                                   1-one,6-ethylene ketal                                       298  6-bromohexanoyl chloride                                                                    1-(9-dimethyl-t-butylsilyloxy-8-oxonon-2-cis-                                  enyl)-4-trimethylsilyloxycyclopent-2-en-1-                                     one,8-ethylene ketal                                         __________________________________________________________________________

EXAMPLES 299-306

By the methods described hereinabove in Examples 268 and 269 and the ketalization reaction described in Example 282, the cyclopent-2-en-1-ones in Table 30 are prepared from the indicated carboxylic acid. By the methods described hereinabove in the sequence of reactions shown in Examples 270-273 and the ketalization reaction described in Example 282 the 4-hydroxy-cyclopent-2-en-1-ones in Table 30 are prepared from the indicated carboxylic acid.

                                      TABLE 30                                     __________________________________________________________________________     Example                                                                             Carboxylic acid      Cyclopent-2-en-1-one                                 __________________________________________________________________________     299  2-(5-carboxypentyl)cyclopent-2-en-1-one                                                             2-(7-hydroxy-6-oxoheptyl)cyclopent-2-en-1-one-                                 6-ethylene ketal                                     300  2-(7-carboxyheptyl)cyclopent-2-en-1-one                                                             2-(9-hydroxy-8-oxononyl)cyclopent-2-en-1-one,-                                 8-ethylene ketal                                     301  2-(6-carboxyhexyl)-4-hydroxycyclopent-2-                                                            2-(8-hydroxy-7-oxooctyl)-4-hydroxycyclopent-2-            en-1-one             en-1-one,7-ethylene ketal                            302  2-(5-carboxypentyl)-4-hydroxycyclopent-2-                                                           2-(7-hydroxy-6-oxoheptyl)-4-hydroxycyclopent-2-                                9                                                         en-1-one             en-1-one,6-ethylene ketal                            303  2-(7-carboxyheptyl)cyclopent-2-en-1-one                                                             2-(9-hydroxy-8-oxononyl)-4-hydroxycyclopent-2-                                 en-1-one,8-ethylene ketal                            304  2-(6-carboxyhex-2-cis-enyl)cyclopent-2-                                                             2-(8-hydroxy-7-oxooct-2-cis-enyl)cyclopent-2-             en-1-one             en-1-one,7-ethylene ketal                            305  2-(5-carboxypent-2-cis-enyl)cyclopent-2-                                                            2-(7-hydroxy-6-oxohept-2-cis-enyl)cyclopent-2-            en-1-one             en-1-one,6-ethylene ketal                            306  2-(7-carboxyhept-2-cis-enyl)cyclopent-2-                                                            2-(9-hydroxy-8-oxonon-2-cis-enyl)cyclopent-2-             en-1-one             en-1-one,8-ethylene ketal                            307  2-(6-carboxyhex-2-cis-enyl)-4(R)-hy-                                                                2-(8-hydroxy-7-oxooct-2-cis-enyl)-4(R)-hydroxy-                                2                                                         droxycyclopent-2-en-1-one                                                                           cyclopent-2-en-1-one,7-ethylene ketal                308  2-(6-carboxyhexyl)-4(R)-hydroxyclo-                                                                 2-(8-hydroxy-7-oxooctyl)-4(R)-hydroxycyclopent-                                .                                                         pent-2-en-1-one      2-en-1-one,7-ethylene ketal                          __________________________________________________________________________

EXAMPLE 309 Preparation of 2-(8-trimethylsilyloxy-7-oxooctyl)-4-trimethylsilyloxycyclopent-2-en-1-one,7-ethylene ketal

To a solution of 2.2 g of 2-(8-hydroxy-7-oxooctyl)-4-hydroxycyclopent-2-en-1-one,7ethylene ketal (Example 301) in 40 ml of pyridine is added 9.2 ml 1,1,1,3,3,3-hexamethyldisilazine and, dropwise, 4.6 ml of trimethylsilylchloride. After 30 minutes, the excess reagents and pyridine are removed at reduced pressure. The residue is taken up in ether and filtered tHrough a short pad of silica gel. The solvent is removed and the residue is dried at reduced pressure to give the title compound.

EXAMPLES 310-318

By the methods described hereinabove in Examples 283 and 309, the hydroxycyclopent-2-en-1-ones listed in Table 31 are converted to their trimethylsilyl ethers shown.

                                      TABLE 31                                     __________________________________________________________________________     Example                                                                             Hydroxycyclopent-2-en-1-one of Example                                                             Protected cyclopent-2-en-1-one                        __________________________________________________________________________     310  299                 2-(7-trimethylsilyloxy-6-oxoheptyl)cyclopent-                                  2-en-1-one,6-ethylene ketal                           311  300                 2-(9-trimethylsilyloxy-8-oxononyl)cyclopent-2-                                 en-1-one,8-ethylene ketal                             312  302                 2-(7-trimethylsilyloxy-6-oxoheptyl)-4-trimeth-                                 ylsilyloxycyclopent-2-en-1-one,6-ethylene                                      ketal                                                 313  303                 2-(9-trimethylsilyloxy-8-oxononyl)-4-trimeth-                                  ylsilyloxycyclopent-2-en-1-one,8-ethylene                                      ketal                                                 314  304                 2-(8-trimethylsilyloxy-8-oxooct-2-cis-enyl)-                                   cyclopent-2-en-1-one,7-ethylene ketal                 315  305                 2-(8-trimethylsilyloxy-6-oxohept-2-cis-enyl)-                                  cyclopent-2-en-1-one,6-ethylene ketal                 316  306                 2-(9-trimethylsilyloxy-8-oxonon-2-cis-enyl)-                                   cyclopent-2-en-1-one,8-ethylene ketal                 317  307                 2-(8-trimethylsilyloxy-7-oxooct-2-cis-enyl)-                                   4(R)-trimethylsilyloxycyclopent-2-en-1-one,7-                                  ethylene ketal                                        318  308                 2-(8-trimethylsilyloxy-7-oxooctyl)-4(R)-tri-                                   methylsilyloxycyclopent-2-en-1-one,7-ethylene                                  ketal                                                 __________________________________________________________________________

EXAMPLE 319 Preparation of 1,9-dioxo-11α,15-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene and 1,9-dioxo-11α,15-epi-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene

To a solution of 1.95 g (0.00533 mol) of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-trans-octene (Example 13) in 6.5 ml of ether is added at -78° C. with stirring under argon 6.66 ml (0.0107 mol) of 1.6 M t-butyllithium in pentane. After 15 minutes at -78° C., the mixture is stirred at -10° to -5° C. for 90 minutes. The solution is cooled to -78° C. and a solution of 0.704 g (0.00533 mol) of copper pentyne and 1.75 g (0.0106 mol) of hexamethylphosphoroustriamide in 20 ml of ether is added. After stirring for one hour, 1.7 g (0.0044 mol) of 2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolon-4-yl)hex-2-cis-enyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-one (Example 281) in 13 ml of ether is added. The solution is maintained at -40° to -50° C. for one hour and -30° C. for 30 minutes. A solution of 1 ml of acetic acid in 5 ml of ether is added followed by a saturated solution of ammonium chloride and dilute hydrochloric acid. The solution is filtered and solids are washed with ether. The combined filtrate is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The ether is removed giving a yellow oil which is dissolved in 60 ml of acetic acid-tetrahydrofuran-water 4:2:1 and heated to 40°-50° C. for 70 minutes. The solvent is removed at reduced pressure at 50° C. The residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The solvent is removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate-benzene 3:2 containing 1% acetic acid to give 0.35 g of 1,9-dioxo-11α,15-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene and 0.39 g of 1,9-dioxo-11α,15-epi-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene.

EXAMPLE 320 Preparation of 1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis-13-trans-prostadiene

To a solution of 2.9 g (5.6 mmol) of (E) 4-trimethylsilyloxy-4-vinyl-1-tri-n-butylstannyloctene (Example 210a) in 4 ml of tetrahydrofuran at -78° C. under argon with stirring is added 2.4 ml of 2.4 M n-butyllithium in hexane. The solution is stirred at -30° to -20° C. for 2 hours. A solution of 0.74 g (5.6 mmol) of copper pentyne and 2.3 ml of hexamethylphosphorous triamide in 18 ml of ether is added at -78° C. The solution is stirred at -78° C. for 1.5 hour. A solution of 2.0 g (5.2 mmol) of 2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-cis-enyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-one (Example 281) in 20 ml of ether is added. The solution is stirred at -30° to - 20° C. for 1.5 hour. To the solution is added 100 ml of saturated ammonium chloride. The mixture is extracted with ether and the ether solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate, and dried over magnesium sulfate. The solvent is removed and the residue is dissolved in 90 ml of acetic acid-tetrahydrofuran-water 4:2:1. The solution is stirred at room temperature for 2 hours. The solvents are removed at reduced pressure at 50° C. Toluene was added and removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate to give 0.5 g of the title compound.

EXAMPLES 321-422

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 32 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one. In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 32; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 32                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example   1,9-dioxo-1-hydroxymethylprostene              321  319   281         49       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     - -    methyl-16,16-trimethylene-20-nor-5-                                     cis-13-trans-prostadiene                       322  319   281         50       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-16,16-trimethylene-20-methyl-5-                                         cis-13-trans-prostadiene                       333  319   281         51       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     -                                                                              methyl-16,16-trimethylene-20-ethyl-5-                                          cis-13-trans-prostadiene                       334  320   281        199       1,9-dioxo-11α,16-dihydroxy-16-cyclo-                                     propyl-20-ethyl-1-hydroxymethyl-5-cis-                                         13-trans-prostadiene                           335  320   281        201       1,9-dioxo-11α,16-hydroxy-16-vinyl-20                                     -                                                                              ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                    336a 320   281        198       1,9-dioxo-11α,16-dihydroxy-16-cyclo-                                     propyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                    336b 320   281        210c      1,9-dioxo-11α,16-dihydroxy-16-ethyl-                                     1-                                                                             hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                            337  319   281        74        dl-erythro-1,9-dioxo-11α,15-dihydrox                                     y-                                                                             16-methoxy-1-hydroxymethyl-5-cis-13-                                           trans-prostadiene                              338  319   281        77        dl-erythro-1,9-dioxo-11α,15-dihydrox                                     y-                                                                             16-ethoxy-1-hydroxymethyl-5-cis-13-                                            trans-prostadiene                              339  319   281        83        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-20-nor-5-cis-13-                                         trans-prostadiene                              340  319   281        84        dl-erythro-1,9-dioxo-11α                                                 ,15,16-trihy-                                                                  droxy-1-hydroxymethyl-20-methyl-5-cis-                                         13-trans-prostadiene                           341  319   281        85        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-20-ethyl-5-cis-                                          13-trans-prostadiene                           342  319   281        86        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-19-methyl-1-hydroxymethyl-5-cis-                                         13-trans-prostadiene                           343  319   281        87        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-5-cis-13-trans-                                          17-trans-prostatriene                          344  319   281        69        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      droxy-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                    345  319   281        88        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      droxy-20-nor-1-hydroxymethyl-5-cis-13-                                         trans-prostadiene                              346  319   281        76        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                    347  319   281        89        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      droxy-20-methyl-1-hydroxymethyl-5-cis-                                         13-trans-prostadiene                           348  319   281        90        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      droxy-20-ethyl-1-hydroxymethyl-5-cis-                                          13-trans-prostadiene                           349  319   281        91        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      droxy-19-methyl-1-hydroxymethyl-5-cis-                                         13-trans-prostadiene                           350  319   281        92        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      droxy-1-hydroxymethyl-5-cis-13-trans-                                          17-trans-prostatriene                          351  319   281        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-5-cis-13-trans-prostadiene              352  319   281        108       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-19,20-dinor-5-cis-13-trans-                                             prostadiene                                    353  319   281        109       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-18,19,20-dinor-5-cis-13-trans-                                          prostadiene                                    354  319   281        110       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-20-nor-5-cis-13-trans-prosta                                            diene                                          355  319   281        144       1,9-dioxo-11α,16-dihydroxy-17-methyl                                     -                                                                              1-hydroxymethyl-5-cis-13-trans-prosta-                                         diene                                          356  319   281        112       1,9-dioxo-11α,16-dihydroxy-20-methyl                                     -                                                                              1-hydroxymethyl-5-cis-13-trans-prosta-                                         diene                                          357  319   281        113       1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                     1-                                                                             hydroxymethyl-5-cis-13-trans-prosta-                                           diene                                          358  319   281        139a      1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -                                                                              20-ethyl-1-hydroxymethyl-5-cis-13-                                             trans-prostadiene                              359  319   281        115       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-13-trans-17-cis-5-cis-prostatri-                                        ene                                            360  319   281        135       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                            361  319   281        136       1,9-dioxo-11α,16-dihydroxy-17,17,20-                                     trimethyl-1-hydroxymethyl-5-cis-13-                                            trans-prostadiene                              362  319   281        137       1,9-dioxo-11α,16-dihydroxy-16,20-dim                                     eth-                                                                           yl-1-hydroxymethyl-13-trans-5-cis-pro-                                         stadiene                                       363  319   281        138       1,9-dioxo-11α,16-dihydroxy-17,17-di-                                     methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                    364  319   281        139       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -                                                                              1-hydroxymethyl-13-trans-17-trans-5-                                           cis-prostatriene                               365  319   281        149       1,9-dioxo-11α,16-dihydroxy-20-methyl                                     -                                                                              1-hydroxymethyl-13-trans-17-trans-5-                                           cis-prostatriene                               366  319   281        150       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -                                                                              1-hydroxymethyl-5-cis-13-trans-prosta-                                         diene                                          367  319   281        151       1,9-dioxo-11α,16-dihydroxy-17,20-di-                                     methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                    368  319   281        152       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     -                                                                              methyl-13-trans-17-trans-5-cis-prosta-                                         triene                                         369  319   281        153       1,9-dioxo-11α,16(R)-dihydroxy-1-hydr                                     oxy-                                                                           methyl-5-cis-13-trans-prostadiene              370  319   281        154       1,9-dioxo-11α,16(S)-dihydroxy-1-hydr                                     oxy-                                                                           methyl-5-cis-13-trans-prostadiene              371  319   281        148a      1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                     1-                                                                             hydroxymethyl-5-cis-13-trans-17-trans-                                         prostatriene                                   372  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1-                                     hydroxy-                                                             phenylmethoxy-1-                                                                         methyl-5-cis-13-trans-prostadiene                                    S. Pat. No.                                                                    3,873,607).                                              373  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-20                                     -methyl-                                                             phenylmethoxy-                                                                           1-hydroxymethyl-5-cis-13-trans-prost-                                (U.S. Pat. No.                                                                 3,873,607).                                              374  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-20                                     -ethyl-1-                                                            phenylmethoxy-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                               1-trans-decene                                                                           ene                                                                  (U.S. Pat. No.                                                                 3,873,607).                                              375  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-di-                                                              phenylmethoxy-                                                                           methyl-1-hydroxymethyl-5-cis-13-trans-                               4,4-dimethyl-                                                                            prostadiene                                                          1-trans-octene                                                                 (U.S. Pat. No.                                                                 3,873,607).                                              376  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-17                                     ,17-di-                                                              phenylmethoxy-                                                                           methyl-1-hydroxymethyl-5-cis-13-trans-                               5,5-dimethyl-                                                                            prostadiene                                                          1-trans-octene                                                                 (U.S. Pat. No.                                                                 3,873,607).                                              377  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     -methyl-                                                             phenylmethoxy-                                                                           1-hydroxymethyl-5-cis-13-trans-prosta-                               4-methyl-1-                                                                              diene                                                                trans-octene                                                                   (U.S. Pat. No.                                                                 3,876,690).                                              378  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     -ethyl-                                                              phenylmethoxy-                                                                           1-hydroxymethyl-5-cis-13-trans-prosta-                               4-ethyl-1-trans-                                                                         diene                                                                octene (U.S.                                                                   Pat. No.                                                                       3,876,690).                                              379  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-17                                     ,20-                                                                 phenylmethoxy-4-                                                                         tetra-nor-16-cyclopentyl-1-hydroxy-                                  cyclopentyl-1-                                                                           methyl-5-cis-13-trans-prostadiene                                    trans-butene-                                                                  (U.S. Pat. No.                                                                 3,884,969).                                              380  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     ,20-                                                                 Phenylmethoxy-3-                                                                         pentanor-16-cyclohexyl-1-hydroxymethyl-                              cyclohexyl-1-                                                                            r-cis-13-trans-prostadiene                                           trans-pentene                                                                  (U.S. Pat. No.                                                                 3,884,969).                                              381  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-18                                     ,20-tri-                                                             phenylmethoxy-                                                                           nor-17-cyclohexyl-1-hydroxymethyl-5-cis-                             5-cyclohexyl-1-                                                                          13-trans-prostadiene                                                 trans-pentene                                                                  (U.S. Pat. No.                                                                 3,884,969).                                              382  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-19                                     ,20-dinor-                                                           phenylmethoxy-6-                                                                         18-cyclopentyl-1-hydroxymethyl-5-cis-                                cyclopentyl-1-                                                                           13-trans-prostadiene                                                 trans-hexene                                                                   (U.S. Pat. No.                                                                 3,884,969).                                              383  319   281        1-iodo-3-methyl-                                                                         1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-                                                             3-trimethylsilyl-                                                                        1-hydroxymethyl-5-cis-13-trans-prosta-                               oxy-trans-1-octene                                                                       diene                                                                (Example 125)                                            384  319   281        1-iodo-3-methyl-                                                                         1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-                                                             3-trimethylsilyl-                                                                        20-ethyl-1-hydroxymethyl-5-cis-13-                                   oxy-trans-1-decene                                                                       trans-prostadiene                                                    (Example 190a)                                           385  320   281        159       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-p-fluorophenoxy-1-                                              hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                            386  320   281        186       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-phenoxy-1-hydroxymethyl-                                        5-cis-14-trans-prostadiene                     387  320   281        181       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-p-bromophenoxy-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene              388  320   281        182       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-p-6-butylphenoxy-1-hy-                                          droxymethyl-5-cis-13-trans-prostadiene         389  320   281        183       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                             20-tetranor-16-p-methoxyphenoxy-1-hy-                                                    droxymethyl-5-cis-13-trans-prostadiene         390  320   281        184       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-m-chlorophenoxy-1-hy-                                           droxymethyl-5-cis-13-trans-prostadiene         391  320   281        180       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-m-trifluorophenoxy-1-hy-                                        droxymethyl-5-cis-13-trans-prostadiene         392  320   281        185       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,-                                                                       20-tetranor-16-(3,4-dichlorophenoxy)-                                          1-hydroxymethyl-5-cis-13-trans-prosta-                                         diene                                          393  320   281        186b      1,9-dioxo-11α ,15α-dihydroxy-1                                     8,19,20-                                                                       trinor-17-phenyl-1-hydroxymethyl-5-                                            cis-13-trans-prostadiene                       394  320   281        186e      1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-                                                                        trinor-17-(m-trifluoromethylphenyl)-1-                                         hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                            395  320   281        186d      1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-                                                                        trinor-17-(p-methoxyphenyl)-1-hydroxy-                                         methyl-5-cis-13-trans-prostadiene              396  319   290        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-1-                                     hydroxy-                                                             ylmethoxy-1-trans-                                                                       methyl-2-nor-5-cis-13-trans-prostadiene                              octene (U.S. Pat.                                                              3,873,607)                                               397  319   290        190       1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-                                                                       1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene                                    398  319   290        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-di-                                                              ylmethoxy-5,5-di-                                                                        methyl-1-hydroxymethyl-2-nor-5-cis-13-                               methyl octene (U.S                                                                       trans-prostadiene                                                    Pat. 3,873,607)                                          399  319   290        13        1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-tri-                                                                       methylene-1-hydroxymethyl-2-nor-5-cis-                                         13-trans-prostadiene                           400  319   290        76        erythro-1,9-dioxo-11α,15-60                                              ,16-trihydroxy- -    1-hydroxymethyl-2-nor                                     -5-cis-13-trans-                                                               prostadiene                                    401  319   290        69        threo-1,9-dioxo-11α,15α-trihyd                                     roxy-                                                                          1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene                                    402  319   290        74        erythro-1,9-dioxo-11α,15α-dihy                                     droxy-16-                                                                      methoxy-1-hydroxymethyl-2-nor-5-cis-13-                                        trans-prostadiene                              403  319   290        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     - -    methyl-2-nor-5-cis-13-trans-prostad                                     iene                                           404  319   290        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-2-nor-5-cis-13-trans-                                            prostadiene                                    405  319   290        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -                                                                              1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene                                    406  320   290        186       1,9-dioxo-11α,15α-dihydroxy-2,                                     17,18,-                                                                        19,20-pentanor-16-phenoxy-1-hydroxy-                                           methyl-5-cis-13-trans-prostadiene              407  320   290        180       1,9-dioxo-11α,15α-dihydroxy-2,                                     17,18,-                                                                        19,20-pentanor-16-m-trifluoromethyl-                                           phenoxy-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                    408  319   290        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-                                                                             hydroxymethyl-2-nor-5-cis-13-trans-                                            prostadiene                                    409  320   290        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     ro-                                                                            pyl-1-hydroxymethyl-2-nor-5-cis-13-                                            trans-prostadiene                              410  320   290        186b      1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,-                                                                        20-tetranor-17-phenyl-1-hydroxymethyl-                                         5-cis-13-trans-prostadiene                     411  319   290        186e      1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,-                                                                        20-tetranor-17-(m-trifluorohenyl)-1-                                           hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                            412  319   290        186d      1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,-                                                                        20-tetranor-17-(p-methoxyphenyl)-1-                                            hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                            413  319   285        125       1,9-dioxo-15-hydroxy-15-methyl-1-hy-                                           droxymethyl-2-nor-13-trans-prostene            414  319   289        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -                                                                              1-homo-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                    415  319   289        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -                                                                              1-homo-1-hydroxymethyl-5-cis-13-trans-                                         17-trans-prostatriene                          416  320   289        186       1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-17,-                                                                      18,19,20-tetranor-16-phenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene              417  320   289        180       1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-17,-                                                                      18,19,20-tetranor-16-m-trifluoromethyl-                                        phenoxy-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                    418  319   289        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-                                                                             homo-1-hydroxymethyl-5-cis-13-trans-                                           prostadiene                                    419  320   289        198       1,9-dioxo-11α,16-dihydroxy-16-cyclo-                                     propyl-1-homo-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene                              420  320   289        186b      1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-18,-                                                                      19,20-trinor-17-phenyl-1-hydroxymethyl-                                        5-cis-13-trans-prostadiene                     421  319   289        186e      1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-18,-                                                                      19,20-trinor-17-(m-trifluorophenyl)-13-                                        trans-1-hydroxymethyl-5-cis-prostadiene        422  319   289        186d      1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-18,-                                                                      19,20-trinor-17-(p-methoxyphenyl)-13-                                          trans-1-hydroxymethyl-5-cis-prostadiene        __________________________________________________________________________

EXAMPLES 423-445

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 33 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 33. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃. . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      TABLE 33                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tin of                                                                           1,9-dioxo-1-hydroxymethylprostene and            Example                                                                             Example                                                                              of Example Example its diastereomer                                 __________________________________________________________________________     423  319   281        246     nat(and ent)-1,9-dioxo-11α,15-dihydrox                                   y-                                                                             15,16-tetramethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-5-cis,13-trans-                                            prostadiene                                      424  320   281        245     nat(and ent)-1,9-dioxo-11α,16-dihydrox                                   y-                                                                             16,17-tetramethylene-18,19,20-trinor-1-                                        hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                              425  319   281        243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-                                        11α,16-dihydroxy-15,16-trimethylene-1-                                   hydroxymethyl-5-cis-13-trans-prostadi-                                         ene                                              426  319   281        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   hydroxymethyl-13-trans-5-cis-prostadiene         427  319   281        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-                                     hydroxymethyl-13-trans-5-cis-prostadiene         428  319   281        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-trimethylene-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene                                              429  320   281        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-pentamethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-5-cis-                                            prostadiene                                      430  319   281        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-                                    hydroxymethyl-13-trans-5-cis-prostadiene         431  319   281        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-                                    N                                                                              droxymethyl-13-trans-5-cis-prostadiene           432  319   281        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   1-                                                                             hydroxymethyl-13-trans-5-cis-prostadiene         433  319   281        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   1-                                                                             hydroxymethyl-13-trans-5-cis-prostadiene         434  320   281        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene                                      435  320   281        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene                                      436  319   281        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene                                              437  319   281        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-         438  320   281        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene                                              439  320   281        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene                                              440  319   281        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-                                     20-dinor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene                                      441  319   281        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene                                      442  320   281        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-2-                                   O                                                                              methyl-1-hydroxymethyl-13-trans-5-cis-                                         prostadiene                                      443  320   281        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-20                                   -                                                                              methyl-1-hydroxymethyl-13-trans-5-cis-                                         prostadiene                                      444  320   281        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-tri-                                       nor-1-hydroxymethyl-13-trans-5-cis-                                            prostadiene                                      445  320   281        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-tri-                                       nor-1-hydroxymethyl-13-trans-5-cis-                                            prostadiene                                      __________________________________________________________________________

EXAMPLES 446-530

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 34 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers is listed in Table 34; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 34                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example   1,9-dioxo-1-hydroxymethylprostene              __________________________________________________________________________     446  319   292        49        1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16,16-trimethylene-20-nor-13-trans-                                         prostene                                       447  319   292        50        1,9-dioxo-11α-15-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16,16-trimethylene-20-methyl-13-trans-                                      N                                                                              prostene                                       448  319   292        51        1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16,16-trimethylene-20-ethyl-13-trans-                                       prostene                                       449  320   292        193       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     ro-                                                                            pyl-20-ethyl-1-hydroxymethyl-13-trans-                                         prostene                                       450  320   292        195       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     20-                                                                            ethyl-1-hydroxymethyl-13-trans-prostene        451  320   292        192       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     ro-                                                                            pyl-1-hydroxymethyl-13-trans-prostene          452  319   292        13        1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16,16-trimethylene-13-trans-prostene        453  320   292        210a      1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16-vinyl-13-trans-prostene                  454  319   292        74        dl-erythro-1,9-dioxo-11α,15-dihydrox                                     y-16-                                                                          methoxy-1-hydroxymethyl-13-trans-prost-                                        ene                                             455a                                                                               319   292        77        dl-erythro-1,9-dioxo-11α,15-dihydrox                                     y-16-                                                                          ethoxy-1-hydroxymethyl-13-trans-prostene        455b                                                                               320   292        210c      1,9-dioxo-11α,16-dihydroxy-16-ethyl-                                     1-hy-                                                                          droxymethyl-13-trans-prostene                  456  319   292        83        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-20-nor-13-trans-                                         prostene                                       457  319   292        84        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-20-methyl-13-trans-                                      prostene                                       458  319   292        85        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-20-ethyl-1-hydroxymethyl-13-trans-                                       prostene                                       459  319   292        86        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-19-methyl-1-hydroxymethyl-13-trans-                                      N                                                                              prostene                                       460  319   292        87        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-13-trans-17-trans-                                       prostadiene                                    461  319   292        69        dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           1-hydroxymethyl-13-trans-prostene              462  319   292        88        dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           20-nor-1-hydroxymethyl-13-trans-prostene       463  319   292        76        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     -                                                                              droxy-1-hydroxymethyl-13-trans-prostene        464  319   292        89        dl-threo-1,9-dioxo-11α,15,16-trihy-                                      A                                                                              20-methyl-1-hydroxymethyl-13-trans-pro-                                        stene                                          465  319   292        90        dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           20-ethyl-1-hydroxymethyl-13-trans-prost-                                       ene                                            466  319   292        91        dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           19-methyl-1-hydroxymethyl-13-trans-pro-                                        stene                                          467  319   292        92        dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           1-hydroxymethyl-13-trans-17-trans-pro-                                         stadiene                                       468  319   292        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-13-trans-prostene                           469  319   292        108       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-19,20-dinor-13-trans-prostene               470  319   292        109       1,9-dioxo-11α ,16-dihydroxy-1-hydrox                                     ymeth-                                                                         yl-18,19,20-trinor-13-trans-prostene           471  319   292        110       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-20-nor-13-trans-prostene                    472  319   292        144       1,9-dioxo-11α,16-dihydroxy-17-methyl                                     -1-                                                                            hydroxymethyl-13-trans-prostene                473  319   292        112       1,9-dioxo-11α,16-dihydroxy-20-methyl                                     -1-                                                                            hydroxymethyl-13-trans-prostene                474  319   292        113       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-hy-                                                                         droxymethyl-13-trans-prostene                  475  319   292        139a      1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -20-                                                                           ethyl-1-hydroxymethyl-13-trans-prostene        476  319   292        115       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-13-trans-17-cis-prostadiene                 477  319   292        135       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-13-trans-prostene                478  319   292        136       1,9-dioxo-11α,16-dihydroxy-17,17,20-                                     tri-                                                                           methyl-1-hydroxymethyl-13-trans-prostene       479  319   292        137       1,9-dioxo-11α,16-dihydroxy-16,20-dim                                     eth-                                                                           yl-1-hydroxymethyl-13-trans-prostene           480  319   292        138       1,9-dioxo-11α,16-dihydroxy-17,17-dim                                     eth-                                                                           yl-1-hydroxymethyl-13-trans-prostene           481  319   292        139       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-13-trans-17-trans-prosta-                                        diene                                          482  319   292        149       1,9-dioxo-11α,16-dihydroxy-20-methyl                                     -1-                                                                            hydroxymethyl-13-trans-17-trans-prosta-                                        diene                                          483  319   292        150       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-13-trans-prostene                485  319   292        151       1,9-dioxo-11α,16-dihydroxy-17,20-dim                                     eth-                                                                           yl-1-hydroxymethyl-13-trans-prostene           486  319   292        152       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-13-trans-17-trans-prostadiene               487  319   292        153       1,9-dioxo-11α,16(R)-dihydroxy-1-hydr                                     oxy-                                                                           methyl-13-trans-prostene                       488  319   292        154       1,9-dioxo-11α,16(S)-dihydroxy-1-hydr                                     oxy-                                                                           methyl-13-trans-prostene                       489  319   292        148a      1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                     1-hy-                                                                          droxymethyl-13-trans-17-trans-prostadiene      490  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α, 15α-dihydroxy-1                                     -hydroxy-                                                            phenylmethoxy-                                                                           methyl-13-trans-prostadiene                                          1-trans-octene                                                                 (U.S. Pat. No.                                                                 3,873,607).                                              491  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-20                                     -methyl-1-                                                           phenylmethoxy-1-                                                                         hydroxymethyl-13-trans-prostene                                      trans-nonene                                                                   (U.S. Pat. No.                                                                 3,873,607).                                              492  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-20                                     -ethyl-1-                                                            phenylmethoxy-                                                                           hydroxymethyl-13-trans-prostene                                      1-trans-decene                                                                 (U.S. Pat. No.                                                                 3,873,607).                                              493  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-dimeth-                                                          phenylmethoxy-                                                                           yl-1-hydroxymethyl-13-trans-prostene                                 4,4-dimethyl-1-                                                                trans-octene                                                                   (U.S. Pat. No.                                                                 3,873,607).                                              494  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-17                                     ,17-dimeth-                                                          phenylmethoxy-                                                                           yl-1-hydroxymethyl-13-trans-prostene                                 5,5-dimethyl-1-                                                                trans-octene                                                                   (U.S. Pat. No.                                                                 3,873,607).                                              495  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     -methyl-                                                             phenylmethoxy-                                                                           hydroxymethyl-13-trans-prostene                                      4-methyl-1-                                                                    trans-octene                                                                   (U.S. Pat. No.                                                                 3,876,690).                                              496  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     -ethyl-                                                              phenylmethoxy-                                                                           hydroxymethyl-13-trans-prostene                                      4-ethyl-1-                                                                     trans-octene                                                                   (U.S. Pat. No.                                                                 3,876,690).                                              497  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-17                                     ,20-tetra-                                                           phenylmethoxy-                                                                           nor-16-cyclopentyl-1-hydroxymethyl-13-                               4-cyclopentyl-                                                                           trans-prostene                                                       1-trans-butene-                                                                (U.S. Pat. No.                                                                 3,884,969).                                              498  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,16α-dihydroxy-16                                     ,20-penta-                                                           phenylmethoxy-                                                                           nor-15-cyclohexyl-1-hydroxymethyl-13-                                3-cyclohexyl-                                                                            trans-prostene                                                       1-trans-pentene                                                                (U.S. Pat. No.                                                                 3,884,969).                                              499  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-18                                     ,20-trinor-                                                          phenylmethoxy-                                                                           17-cyclohexyl-1-hydroxymethyl-13-trans-                              5-cyclohexyl-                                                                            prostene                                                             1-trans-pentene                                                                (U.S. Pat. No.                                                                 3,884,969).                                              500  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-19                                     ,20-dinor-                                                           phenylmethoxy-                                                                           18-cyclopentyl-1-hydroxymethyl-13-trans-                             6-cyclopentyl-                                                                           prostene                                                             1-trans-hexene                                                                 (U.S. Pat. No.                                                                 3,884,969).                                              501  319   292        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-1-                                                           methylsilyloxy-                                                                          hydroxymethyl-13-trans-prostene                                      trans-1-octene                                                                 (Example 125)                                            502  319   292        1-iodo-3-methyl-                                                                         1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-20-                                                          3-trimethylsilyl-                                                                        ethyl-1-hydroxymethyl-13-trans-prostene                              oxy-trans-1-decene                                                             (Example 190a)                                           503  320   292        159       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-fluorophenoxy-1-hydroxy-                                         methyl-13-trans-prostene                       504  320   292        186       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-phenoxy-1-hydroxymethyl-13-                                        trans-prostene                                 505  320   292        181       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-bromophenoxy-1-hydroxy-                                          methyl-13-trans-prostene                       506  320   292        182       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-t-butylphenoxy-1-hydroxy-                                        methyl-13-trans-prostene                       507  320   292        183       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-methoxyphenoxy-1-hydroxy-                                        methyl-13-trans-prostene                       508  320   292        184       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-m-chlorophenoxy-1-hydroxy-                                         methyl-13-trans-prostene                       509  320   292        180       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-m-trifluorophenoxy-1-hydr-                                         oxymethyl-13-trans-prostene                    510  320   292        185       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-(3,4-dichlorophenoxy)-1-hy-                                        droxymethyl-13-trans-prostene                  511  320   292        186b      1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-tri-                                                                    nor-17-phenyl-1-hydroxymethyl-13-trans-                                        prostene                                       512  320   292        186e      1,9-dioxo-11α,15α-dihdroxy-18,                                     19,20-tri-                                                                     nor-17-(m-trifluoromethylphenyl)-1-hy-                                         droxy-13-trans-prostene                        513  320   292        186d      1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-tri-                                                                    nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                      13-trans-prostene                              514  319   293        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1-                                     hydroxy-                                                             phenylmethoxy-                                                                           methyl-trans-prostadiene                                             1-trans-octene                                                                 (U.S. Pat. No.                                                                 3,873,607).                                              515  319   293        190       1,9-dioxo-11α,15α                                                  -dihydroxy-15-methyl-1-                                                        hydroxymethyl-2-nor-13-trans-prostene          516  319   293        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-di-                                                              phenylmethoxy-                                                                           methyl-1-hydroxymethyl-2-nor-13-trans-                               5,5-dimethyl-                                                                            prostene                                                             octenet (U.S.                                                                  Pat. No. 3,873,607)                                      517  319   293        13        1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-tri-                                                                       methylene-1-hydroxymethyl-2-nor-13-trans-                                      prostene                                       518  319   293        76        erythro-1,9-dioxo-11α,15α,16-t                                     rihydroxy-                                                                     1-hydroxymethyl-2-nor-13-trans-prostene        519  319   293        69        threo-1,9-dioxo-11α,15α,                                           16-trihydroxy-1-                                                               hydroxymethyl-2-nor-13-trans-prostene          520  319   293        74        erythro-1,9-dioxo-11α,15α-dihy                                     droxy-16-                                                                      methoxy-1-hydroxymethyl-2-nor-13-trans-                                        prostene                                       521  319   293        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-2-nor-13-trans-prostene                     522  319   293        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-2-nor-13-trans-prostene          523  319   293        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-2-nor-13-trans-prostene          524  320   293        186       1,9-dioxo-11α,15α-dihydroxy-2,                                     17,18,19,                                                                      20-pentanor-16-phenoxy-1-hydroxymethyl-                                        13-trans-prostene                              525  320   293        180       1,9-dioxo-11α,15α-dihydroxy-2,                                     17,18,19,-                                                                     20-pentanor-16-m-trifluoromethylphenoxy-                                       1-hydroxymethyl-13-trans-prostene              526  319   293        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-                                                                             hydroxymethyl-2-nor-13-trans-prostene          527  320   293        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     rop-                                                                           yl-1-hydroxymethyl-2-nor-13-trans-prost-                                       ene                                            528  320   293        186b      1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,20-                                                                      tetrano-17-phenyl-1-hydroxymethyl-13-                                          trans-prostene                                 529  319   293        186e      1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,20-                                                                      tetranor-17-(m-trifluorophenyl)-1-hy-                                          droxymethyl-13-trans-prostene                  530  319   293        186d      1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,20-                                                                      tetranor-17-(p-methoxyphenyl)-1-hy-                                            droxymethyl-13-trans-prostene)                 __________________________________________________________________________

EXAMPLES 531-553

By the method described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 35 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 35. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃. . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      TABLE 35                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tin of                                                                           1,9-dioxo-1-hydroxymethylprostene and            Example                                                                             Example                                                                              of Example Example its diastereomer                                 __________________________________________________________________________     531  319   292        246     nat(and ent)-1,9-dioxo-11α,15-dihydrox                                   y-                                                                             15,16-tetramethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-prostene            532  320   292        245     nat(and ent)-1,9-dioxo-11α,16-dihydrox                                   y-                                                                             16,17-tetramethylene-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-prostene                  533  319   292        243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-                                        11α,15-dihydroxy-15,16-trimethylene-1-                                   b                                                                              hydroxymethyl-13-trans-prostene                  534  319   292        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   N                                                                              hydroxymethyl-13-trans-prostene                  535  319   292        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   O                                                                              hydroxymethyl-13-trans-prostene                  536  319   292        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-trimethylene-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene                537  320   292        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-pentamethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-prostene            538  319   292        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-                                    M                                                                              hydroxymethyl-13-trans-prostene                  539  319   292        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-h                                   y-                                                                             droxymethyl-13-trans-prostene                    540  319   292        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   1-                                                                             hydroxymethyl-13-trans-prostene                  541  319   292        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   0                                                                              hydroxymethyl-13-trans-prostene                  542  320   292        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-prost-                                       ene                                              543  320   292        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-prost-                                       ene                                              544  319   292        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene                545  319   292        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene                546  320   292        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene                547  320   292        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene                548  319   292        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-trans-prost-                                       ene                                              549  319   292        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-trans-prost-                                       ene                                              550  320   292        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-20                                   -                                                                              methyl-1-hydroxymethyl-13-trans-prostene         551  320   292        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-20                                   -                                                                              methyl-1-hydroxymethyl-13-trans-prostene         552  320   292        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-tri-                                       nor-1-hydroxymethyl-13-trans-prostene            553  320   292        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-tri-                                       nor-1-hydroxymethyl-13-trans-prostene            __________________________________________________________________________

EXAMPLES 554-637

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 36 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 36; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomer is also formed and is part of this invention.

In those cases where the initial conjugate addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 36                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example    1,9-dioxo-1-hydroxymethylprostene             __________________________________________________________________________     554  319   287        49         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      N                                                                              16-trimethylene-20-nor-5-cis-13-trans-                                         prostadiene                                   555  319   287        50         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      O                                                                              16-trimethylene-20-methyl-5-cis-13-trans-                                      u                                                                              prostadiene                                   556  319   287        51         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      n                                                                              16-trimethylene-20-ethyl-5-cis-13-trans-                                       0                                                                              prostadiene                                   557  320   287        193        1,9-dioxo-16-hydroxy-16-cyclopropyl-20-                                        ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                   558  320   287        195        1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1-                                      6                                                                              hydroxymethyl-5-cis-13-trans-prostadiene                                       J                                             559  320   287        192        1,9-dioxo-11α,16-dihydroxy-16-cyclo                                      propyl-                                                                        1-hydroxymethyl-5-cis-13-trans-prostadi-                                       l                                                                              ene                                           560  319   287        13         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      0                                                                              16-trimethylene-13-trans-5-cis-prostadien                                      e                                             561  320   287        210a       1,9-dioxo-16-hydroxy-1-hydroxymethyl-16                                        vinyl-5-cis-13-trans-prostadiene              562  319   287        74         dl-erythro-1,9-dioxo-15-hydroxy-16-meth-                                       A                                                                              oxy-1-hydroxymethyl-5-cis-13-trans-prosta                                      -                                                                              diene                                         563  319   287        77         dl-erythro-1,9-dioxo-15-hydroxy-16-ethoxy                                      -                                                                              1-hydroxymethyl-5-cis-13-trans-prostadi-                                       0                                                                              ene                                           564  319   287        83         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-nor-5-cis-13-trans-                                           prostadiene                                   565  319   287        84         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-methyl-5-cis-13-trans-                                        prostadiene                                   566  319   287        85         dl-erythro-1,9-dioxo-15,16-dihydroxy-2-                                        ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                   567  319   287        86         dl-erythro-1,9-dioxo-15,16-dihydroxy-19-                                       8                                                                              methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                   568  319   287        87         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-5-cis-13-trans-17-trans-                                         prostatriene                                  569  319   287        69         dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                       S                                                                              droxymethyl-5-cis-13-trans-prostadiene        570  319   287        88         dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         nor-1-hydroxymethyl-5-cis-13-trans-                                            prostadiene                                   571  319   287        76         dl-erythro-1,9-dioxo-11α,15,16-trih                                      y-                                                                             droxy-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                   572  319   287        89         dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                   573  319   287        90         dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                   574  319   287        91         dl-threo-1,9-dioxo-15,16-dihydroxy-19-                                         methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                   575  319   287        92         dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                       p                                                                              droxymethyl-5-cis-13-trans-17-trans-                                           prostatriene                                  576  319   287        107        1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          cis-13-trans-prostadiene                      577  319   287        108        1,9-dioxo-16-hydroxy-1-hydroxymethyl-19,-                                      0                                                                              20-dinor-5-cis-13-trans-prostadiene           578  319   287        109        1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                      9                                                                              19,20-trinor-5-cis-13-trans-prostadiene       579  319   287        110        1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                       N                                                                              nor-5-cis-13-trans-prostadiene                580  319   297        144        1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy-                                      O                                                                              methyl-5-cis-13-trans-prostadiene             581  319   287        112        1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                      O                                                                              methyl-5-cis-13-trans-prostadiene             582  319   287        113        1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                       c                                                                              methyl-5-cis-13-trans-prostadiene             583  319   287        139a       1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                       t                                                                              1-hydroxymethyl-5-cis-13-trans-prostadi-                                       1                                                                              ene                                           584  319   287        115        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                       0                                                                              trans-17-cis-5-cis-prostatriene               585  319   287        135        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      N                                                                              methyl-5-cis-13-trans-prostadiene             586  319   287        136        1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                       o                                                                              1-hydroxymethyl-5-cis-trans-prostadi-                                          ene                                           587  319   287        137        1,9-dioxo-16-hydroxy-16,20-dimethyl-1-hy-                                      v                                                                              droxymethyl-13-trans-5-cis-prostadiene        588  319   287        138        1,9-dioxo-16-hydroxy-17,17-dimethyl-1-hy-                                      1                                                                              droxymethyl-5-cis-13-trans-prostadiene        589  319   287        139        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      1                                                                              methyl-13-trans-17-trans-5-cis-prostatri-                                      D                                                                              ene                                           590  319   287        149        1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                      e                                                                              methyl-13-trans-17-trans-5-cis-prostatri-                                      c                                                                              ene                                           591  319   287        150        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      1                                                                              methyl-5-cis-13-trans-prostadiene             592  319   287        151        1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                      2                                                                              droxymethyl-5-cis-13-trans-prostadiene        593  319   287        152        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                       trans-17-trans-5-cis-prostatriene             594  319   287        153        1,9-dioxo-16-(R)-hydroxy-1-hydroxymethyl-                                      5-cis-13-trans-prostadiene                    595  319   287        154        1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene                    596  319   287        148a       1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                       methyl-5-cis-13-trans-17-trans-prostatri-                                      ene                                           597  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-1-hydroxymeth                                      yl-5-                                                               ylmethoxy-1-trans-                                                                        cis-13-trans-prostadiene                                            octene (U.S. Pat.                                                              No. 3,873,607).                                          598  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-20-methyl-1-h                                      ydr-                                                                ylmethoxy-1-trans-                                                                        oxymethyl-5-cis-13-trans-prostadiene                                nonene (U.S. Pat.                                                              No. 3,873,607).                                          599  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-20-ethyl-1-hy                                      droxy-                                                              ylmethoxy-1-trans-                                                                        methyl-5-cis-13-trans-prostadiene                                   decene (U.S. Pat.                                                              No. 3,873,607).                                          600  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-16,16-dimethy                                      l-1-                                                                ylmethoxy-4,4-di-                                                                         hydroxymethyl-5-cis-13-trans-prostadiene                                       Z                                                                   methyl-1-trans-                                                                octene (U.S. Pat.                                                              No. 3,873,607).                                          601  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-17,17-dimethy                                      l-1-                                                                ylmethoxy-5,5-di-                                                                         hydroxymethyl-5-cis-13-trans-prostadiene                                       `                                                                   methyl-1-trans-                                                                octene (U.S. Pat.                                                              No. 3,873,607).                                          602  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-16-methyl-1-h                                      ydr-                                                                ylmethoxy-4-meth-                                                                         oxymethyl-5-cis-13-trans-prostadiene                                yl-1-trans-octene                                                              (U.S. Pat. No.                                                                 3,876,690).                                              603  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-16-ethyl-1-hy                                      droxy-                                                              ylmethoxy-4-ethyl-                                                                        methyl-5-cis-13-trans-prostadiene                                   1-trans-octene                                                                 (U.S. Pat. No.                                                                 3,876,690).                                              604  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-17,20-tetrano                                      r-16-                                                               ylmethoxy-4-cyclo-                                                                        cyclopentyl-1-hydroxymethyl-5-cis-13-                               pentyl-1-trans-                                                                           trans-prostadiene                                                   butene (U.S. Pat.                                                              No. 3,884,969).                                          605  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-16,20-pentano                                      r-15-                                                               ylmethoxy-3-cyclo-                                                                        cyclohexyl-1-hydroxymethyl-5-cis-13-                                hexyl-1-trans-                                                                            trans-prostadiene                                                   pentene (U.S. Pat.                                                             No. 3,884,969).                                          606  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-18,20-trinor-                                      17-                                                                 ylmethoxy-5-cyclo-                                                                        cyclohexyl-1-hydroxymethyl-5-cis-13-                                hexyl-1-trans-                                                                            trans-prostadiene                                                   pentene (U.S. Pat.                                                             No. 3,884,969).                                          607  319   287        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-19,20-dinor-1                                      8-                                                                  ylmethoxy-6-cyclo-                                                                        cyclopentyl-1-hydroxymethyl-5-cis-13-                               pentyl-1-trans-                                                                           trans-prostadiene                                                   hexene (U.S. Pat.                                                              No. 3,884,969).                                          608  319   287        1-iodo-3-methyl-3-                                                                        1,9-dioxo-15α-hydroxy-15-methyl-1-h                                      ydr-                                                                trimethylsilyl-                                                                           oxymethyl-5-cis-13-trans-prostadiene                                oxy-trans-1-octene                                       609  319   287        1-iodo-3-methyl-                                                                          1,9-dioxo-15α-hydroxy-15-methyl-20-                                      ethyl-                                                              3-trimethylsil-                                                                           1-hydroxymethyl-5-cis-13-trans-prostadi-                                       v                                                                   yloxy-trans-1-dec-                                                                        ene                                                                 ene (Example 190a).                                      610  320   287        159        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-p-fluorophenoxy-1-hydroxymethyl-5-                                      r                                                                              cis-13-trans-prostadiene                      611  320   287        186        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-phenoxy-1-hydroxymethyl-5-cis-13-                                       e                                                                              trans-prostadiene                             612  320   287        181        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-p-bromophenoxy-1-hydroxymethyl-5-                                       .                                                                              cis-13-trans-prostadiene                      613  320   287        182        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-p-t-butylphenoxy-1-hydroxymethyl-                                       5                                                                              5-cis-13-trans-prostadiene                    614  320   287        183        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                       i                                                                              5-cis-13-trans-prostadiene                    615  320   287        184        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-p-chlorophenoxy-1-hydroxymethyl-                                        5-cis-13-trans-prostadiene                    616  320   287        180        1,9-dioxo-11α,15α-dihydroxy-1                                      7,18,19,20-                                                                    tetranor-m-trifluorophenoxy-1-hydroxy-                                         methyl-5-cis-13-trans-prostadiene             617  320   287        185        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                      etra-                                                                          nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene             618  320   287        186b       1,9-dioxo-15α-hydroxy-18,19,20-trin                                      or-17-                                                                         phenyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                   619  320   287        186e       1,9-dioxo-15α-hydroxy-18,19,20-trin                                      or-17-                                                                         (m-trifluoromethylphenyl)-1-hydroxymeth-                                       Z                                                                              yl-5-cis-13-trans-prostadiene                 620  320   287        186d       1,9-dioxo-15α-hydroxy-18,19,20-trin                                      or-17-                                                                         (p-methoxyphenyl)-1-hydroxymethyl-5-cis-                                       .                                                                              13-trans-prostadiene                          621  319   288        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-dihydroxy-1-hydroxyme                                      thyl-                                                               ylmethoxy-1-trans-                                                                        2-nor-5-cis-13-trans-prostadiene                                    octene (U.S. Pat.                                                              No. 3,873,607).                                          622  319   288        190        1,9-dioxo-15α-hydroxy-15-methyl-1-h                                      ydr-                                                                           oxymethyl-2-nor-5-cis-13-trans-prostadi-                                       t                                                                              ene                                           623  319   288        1-iodo-3-triphen-                                                                         1,9-dioxo-15α-hydroxy-16,16-dimethy                                      l-1-                                                                ylmethoxy-5,5-di-                                                                         hydroxymethyl-2-nor-5-cis-13-trans-                                 methyl octene                                                                             prostadiene                                                         (U.S. Pat. No.                                                                 3,873,607).                                              624  319   288        13         1,9-dioxo-15α-hydroxy-16,16-trimeth                                      ylene-                                                                         1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene                                   625  319   288        76         erythro-1,9-dioxo-15α,16-dihydroxy-                                      1-hy-                                                                          droxymethyl-2-nor-5-cis-13-trans-prosta-                                       n                                                                              diene                                         626  319   288        69         threo-1,9-dioxo-15α,16-dihydroxy-1-                                      hydro-                                                                         xymethyl-2-nor-5-cis-13-trans-prostadiene                                      .                                             627  319   288        74         erythro-1,9-dioxo-15α-hydroxy-16-me                                      th-                                                                            oxy-1-hydroxymethyl-2-nor-5-cis-13-trans-                                      7                                                                              prostadiene                                   628  319   288        107        1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                        nor-5-cis-13-trans-prostadiene                629  319   288        130        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      .                                                                              methyl-2-nor-5-cis-13-trans-prostadiene       630  319   288        134        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      d                                                                              methyl-2-nor-5-cis-13-trans-17-trans-                                          prostatriene                                  631  320   288        186        1,9-dioxo-15α-hydroxy-2,17,18,19,20                                      -pent-                                                                         anor-16-phenoxy-1-hydroxymethyl-5-cis-13-                                      N                                                                              trans-prostadiene                             632  320   288        180        1,9-dioxo-15α-hydroxy-2,17,18,19,20                                      -pent-                                                                         anor-16-m-trifluoromethylphenoxy-1-hydro-                                      f                                                                              xymethyl-5-cis-13-trans-prostadiene           633  319   288        194        1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                       f                                                                              methyl-2-nor-5-cis-13-trans-prostadiene       634  320   288        198        1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                      e                                                                              droxymethyl-2-nor-5-cis-13-trans-prosta-                                       r                                                                              diene                                         635  320   288        186b       1,9-dioxo-15α-hydroxy-2,18,19,20-te                                      tra-                                                                           nor-17-phenyl-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene                             636  319   288        186e       1,9-dioxo-15α-hydroxy-2,18,19,20-te                                      tra-                                                                           nor-17-(m-trifluorophenyl)-1-hydroxymeth-                                      t                                                                              yl-5-cis-13-trans-prostadiene                  637a                                                                               319   288        186d       1,9-dioxo-15α-hydroxy-2,18,19,20-te                                      tra-                                                                           nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                      a                                                                              5-cis-13-trans-prostadiene                     637b                                                                               320   288        210c       1,9-dioxo-16-hydroxy-16-ethyl-1-hydroxy-                                       l                                                                              methyl-2-nor-5-cis-13-trans-prostadiene       __________________________________________________________________________

EXAMPLES 638-660

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 37 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 37. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃. . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

EXAMPLES 661-749

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 38 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 38; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 37                                     __________________________________________________________________________                          Vinyl Iodide or                                                Method of                                                                            Cyclopent-2-en-1-                                                                        Vinyl Tin of                                                                           1,9-dioxo-1-hydroxymethylprostene and             Example                                                                             Example                                                                              one of Example                                                                           Example its diastereomer                                  __________________________________________________________________________     638  319   287       246     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      tetramethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-5-cis-13-trans-prostadiene          639  320   287       245     nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                      tetramethylene-18,19,20-trinor-1-hydr-                                         oxymethyl-5-cis-13-trans-prostadiene              640  319   287       243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-                                        15-hydroxy-15,16-trimethylene-1-hydroxy                                        methyl-5-cis-13-trans-prostadiene                 641  319   287       243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene                 642  319   287       251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene                 643  319   287       247     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      trimethylene-17,18,19,20-tetranor-1-hy-                                        droxymethyl-13-trans-5-cis-prostadiene            644  320   287       248     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      pentamethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-5-cis-prostadiene          645  319   287       249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo                                        15-hydroxy-15,17-dimethylene-1-hydroxy                                         methyl-13-trans-5-cis-prostadiene                 646  319   287       250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-5-cis-prostadiene                 647  319   287       252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hy-                                          droxymethyl-13-trans-5-cis-prostadiene            648  319   287       253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hydr-                                        oxymethyl-13-trans-5-cis-prostadiene              649  320   287       254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo                                        15-hydroxy-15,16-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-5-cis-                                            prostadiene                                       650  320   287       255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-5-cis-                                            prostadiene                                       651  319   287       256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(4-flu-                                       orophenoxy)-17,18,19,20-tetranor-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene              652  319   287       257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo                                        15-hydroxy-15,16-trimethylene-16-(4-flu-                                       orophenoxy)-17,18,19,20-tetranor-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene              653  320   287       258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-5-cis-prostadiene          654  320   287       259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-5-cis-prostadiene          655  319   287       260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene                                            656  319   287       261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene                                            657  320   287       262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-20-methyl-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene                                               658  320   287       263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-20-methyl-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene                                               659  320   287       264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-5-cis-prostadiene          660  320   287       265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-5-cis-prostadiene          __________________________________________________________________________

                                      TABLE 38                                     __________________________________________________________________________                             Vinyl Iodide or                                             Method of          Vinyl Tin of                                           Example                                                                             Example                                                                               Cyclopent-2-en-1-one                                                                       Example      1,9-dioxo-1-hydroxymethylprostene         __________________________________________________________________________     662  319    284          49          1,9-dioxo-15-hydroxy-1-hydroxymethyl-                                          16-                                                                            16-trimethylene-20-nor-13-trans-prost                                          ene                                       663  319    284         50           1,9-dioxo-15-hydroxy-1-hydroxymethyl-                                          16-                                                                            16-trimethylene-20-methyl-13-trans-pr                                          ost-                                                                           ene                                       664  319    284         51           1,9-dioxo-15-hydroxy-1-hydroxymethyl-                                          16,-                                                                           16-trimethylene-20-ethyl-13-trans-pro                                          st-                                                                            ene                                       665  320    284         193          1,9-dioxo-16-hydroxy-16-cyclopropyl-2                                          0-                                                                             ethyl-1-hydroxymethyl-13-trans-proste                                          ne                                        666  320    284         195          1,9-dioxo-16-hydroxy-16-vinyl-20-ethy                                          l-1-                                                                           hydroxymethyl-13-trans-prostene           667  320    284         192          1,9-dioxo-16-hydroxy-16-cyclopropyl-1                                          -                                                                              hydroxymethyl-13-trans-prostene           668  319    284         13           1,9-dioxo-15-hydroxy-1-hydroxymethyl-                                          16-                                                                            16-trimethylene-13-trans-prostene         669  320    284         210a         1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          16-                                                                            vinyl-13-trans-prostene                   670  319    284         74           dl-erythro-1,9-dioxo-15-dihydroxy-16-                                          meth-                                                                          oxy-1-hydroxymethyl-13-trans-prostene                                          0                                         671  319    284         77           dl-erythro-1,9-dioxo-16-dihydroxy-16-                                          eth-                                                                           oxy-1-hydroxymethyl-13-trans-prostene                                          1                                         672  319    284         83           dl-erythro-1,9-dioxo-15,16-dihydroxy-                                          1-                                                                             hydroxymethyl-20-nor-13-trans-prosten                                          e                                         673  319    284         84           dl-erythro-1,9-dioxo-15,16-dihydroxy-                                          1-                                                                             hydroxymethyl-20-methyl-13-trans-pros                                          t-                                                                             ene                                       674  319    284         85           dl-erythro-1,9-dioxo-15,16-dihydroxy-                                          20-                                                                            ethyl-1-hydroxymethyl-13-trans-proste                                          ne                                        675  319    284         86           dl-erythro-1,9-dioxo-15,16-dihydroxy-                                          19-                                                                            methyl-1-hydroxymethyl-13-trans-prost                                          ene                                       676  319    284         87           dl-erythro-1,9-dioxo-15,16-dihydroxy-                                          1-                                                                             hydroxymethyl-13-trans-17-trans-prost                                          a-                                                                             diene                                     677  319    284         69           dl-threo-1,9-dioxo-15,16-dihydroxy-1-                                          hy-                                                                            droxymethyl-13-trans-prostene             678  319    284         88           di-threo-1,9-dioxo-15,16-dihydroxy-20                                          -                                                                              nor-1-hydroxymethyl-13-trans-prostene                                          -                                         679  319    284         76           di-erythro-1,9-dioxo-15,16-dihydroxy-                                          1-                                                                             hydroxymethyl-13-trans-prostene           680  319    284         89           dl-threo-1,9-dioxo-15,16-dihydroxy-20                                          -                                                                              methyl-1-hydroxymethyl-13-trans-prost                                          ene                                       681  319    284         90           dl-threo-1,9-dioxo-15,16-dihydroxy-20                                          -                                                                              ethyl-1-hydroxymethyl-13-trans-proste                                          ne                                        682  319    284         91           di-threo-1,9-dioxo-15,16-dihydroxy-19                                          -                                                                              methyl-1-hydroxymethyl-13-trans-prost                                          ene                                       683  319    284         92           dl-threo-1,9-dioxo-15,16-dihydroxy-1-                                          hy-                                                                            droxymethyl-13-trans-17-trans-prostad                                          iene                                      684  319    284         107          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          13-                                                                            trans-prostene                            685  319    284         108          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          19-                                                                            20-dinor-13-trans-prostene                687  319    284         109          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          18,-                                                                           19,20-trinor-13-trans-prostene            688  319    284         110          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          20-                                                                            nor-13-trans-prostene                     689  319    284         144          1,9-dioxo-16-hydroxy-17-methyl-1-hydr                                          oxy-                                                                           methyl-13-trans-prostene                  690  319    284         112          1,9-dioxo-16-hydroxy-20-methyl-1-hydr                                          oxy-                                                                           methyl-13-trans-prostene                  691  319    284         113          1,9-dioxo-16-hydroxy-20-ethyl-1-hydro                                          xy-                                                                            methyl-13-trans-prostene                  692  319    284         139a         1,9-dioxo-16-hydroxy-16-methyl-20-eth                                          yl-                                                                            1-hydroxymethyl-13-trans-prostene         693  319    284         115          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          13-                                                                            trans-17-cis-prostadiene                  694  319    284         135          1,9-dioxo-16-hydroxy-16-methyl-1-hydr                                          oxy-                                                                           methyl-13-trans-prostene                  695  319    284         136          1,9-dioxo-16-hydroxy-17,17,20-trimeth                                          yl-                                                                            1-hydroxymethyl-13-trans-prostene         696  319    284         137          1,9-dioxo-16-hydroxy-16,20-dimethyl-1                                          -                                                                              hydroxymethyl-13-trans-prostene           697  319    284         138          1,9-dioxo-16-hydroxy-17,17-dimethyl-1                                          -                                                                              hydroxymethyl-13-trans-prostene           698  319    284         139          1,9-dioxo-16-hydroxy-16-methyl-1-hydr                                          oxy-                                                                           methyl-13-trans-17-trans-prostadiene                                           Z                                         699  319    284         149          1,9-dioxo-16-hydroxy-20-methyl-1-hydr                                          oxy-                                                                           methyl-13-trans-17-trans-prostadiene                                           8                                         700  319    284         150          1,9-dioxo-16-hydroxy-16-methyl-1-hydr                                          -                                                                              oxymethyl-13-trans-prostene               701  319    284         151          1,9-dioxo-16-hydroxy-17,20-dimethyl-1                                          -hy-                                                                           droxymethyl-13-trans-prostene             702  319    284         152          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          13-                                                                            trans-17-trans-prostadiene                703  319    284         153          1,9-dioxo-16(R)-hydroxy-1-hydroxymeth                                          yl                                                                             13-trans-prostene                         704  319    284         154          1,9-dioxo-16(S)-hydroxy-1-hydroxymeth                                          yl-                                                                            13-trans-prostene                         705  319    284         148a         1,9-dioxo-16-hydroxy-20-ethyl-1-hydro                                          xy-                                                                            methyl-13-trans-17-trans-prostadiene                                           u                                         706  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-1-hydroxy                                          methyl-13-                                                        ylmethoxy-1-trans-                                                                          trans-prostadiene                                                 octene (U.S. Pat.                                                              No. 3,873,607).                                        707  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-20-methyl                                          -1-hydroxy-                                                       ylmethoxy-1-trans-                                                                          methyl-13-trans-prostene                                          nonene (U.S. Pat.                                                              No. 3,873,607).                                        708  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-20-ethyl-                                          1-hydroxy-                                                        ylmethoxy-1-trans-                                                                          methyl-13-trans-prostene                                          decene (U.S. Pat.                                                              No. 3,873,607).                                        709  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-16,16-dim                                          ethyl-1-                                                          ylmethoxy-4,4-di-                                                                           hydroxymethyl-13-trans-prostene                                   methyl-1-trans-oct-                                                            ene (U.S. Pat. No.                                                             3,873,607).                                            710  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-17,17-dim                                          ethyl-1-                                                          ylmethoxy-5,5-di-                                                                           hydroxymethyl-13-trans-prostene                                   methyl-1-trans-oct-                                                            ene (U.S. Pat. No.                                                             3,873,607).                                            711  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-16-methyl                                          -1-hydroxy-                                                       ylmethoxy-4-meth-                                                                           methyl-13-trans-prostene                                          yl-1-trans-octene                                                              (U.S. Pat. No.                                                                 3,876,690).                                            712  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-16-ethyl-                                          1-hydr-                                                           ylmethoxy-4-ethyl-                                                                          oxymethyl-13-trans-prostene                                       1-trans-octene                                                                 (U.S. Pat. No.                                                                 3,876,690).                                            713  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-17,20-tet                                          ranor-16-                                                         ylmethoxy-4-cyclo-                                                                          cyclopentyl-1-hydroxymethyl-13-trans-                                          l                                                                 pentyl-1-trans-                                                                             prostene                                                          butene (U.S. Pat.                                                              No. 3,884,969).                                        714  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-16,20-pen                                          tanor-15-                                                         ylmethoxy-3-cyclo-                                                                          cyclohexyl-1-hydroxymethyl-13-trans-                                           i                                                                 hexyl-1-trans-pen-                                                                          prostene                                                          tene (U.S. Pat. No.                                                            3,884,969).                                            715  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-18,20-tri                                          nor-17-                                                           ylmethoxy-5-cyclo-                                                                          cyclohexyl-1-hydroxymethyl-13-trans-                                           o                                                                 hexyl-1-trans-                                                                              prostene                                                          pentene (U.S. Pat.                                                             No. 3,884,969).                                        716  319    284         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-19,20-din                                          or-18-                                                            ylmethoxy-6-cyclo-                                                                          cyclopentyl-1-hydroxymethyl-13-trans-                                          .                                                                 pentyl-1-trans-                                                                             prostene                                                          hexene (U.S. Pat.                                                              No. 3,884,969).                                        717  319    284         1-iodo-3-methyl-                                                                            1,9-dioxo-15α-hydroxy-15-methyl                                          -1-hydr-                                                          3-trimethylsilyl-                                                                           oxymethyl-13-trans-prostene                                       oxy-trans-1-octene                                                             (Example 125).                                         718  319    284         1-iodo-3-methyl-                                                                            1,9-dioxo-15α-hydroxy-15-methyl                                          -20-ethyl-                                                        3-trimethylsilyl-                                                                           1-hydroxymethyl-13-trans-prostene                                 oxy-trans-1-decene                                                             (Example 190a).                                        719  320    284         159          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-p-fluorophenoxy-1-hydroxymethy                                          l-                                                                             13-trans-prostene                         720  320    284         186          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-phenoxy-1-hydroxymethyl-13-tra                                          ns-                                                                            prostene                                  721  320    284         181          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-p-bromophenoxy-1-hydroxymethyl                                          -13-                                                                           trans-prostene                            722  320    284         182          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-p-t-butylphenoxy-1-hydroxymeth                                          yl-                                                                            13-trans-prostene                         723  320    284         183          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-p-methoxyphenoxy-1-hydroxymeth                                          yl-                                                                            13-trans-prostene                         724  320    284         184          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-m-chlorophenoxy-1-hydroxymethy                                          l-                                                                             13-trans-prostene                         725  320    284         180          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-m-trifluorophenoxy-1-hydroxyme                                          thyl-                                                                          13-trans-prostene                         726  320    284         185          1,9-dioxo-15α-hydroxy-17,18,19,                                          20-tetra-                                                                      nor-16-(3,4-dichlorophenoxy)-1-hydrox                                          y-                                                                             methyl-13-trans-prostene                  727  320    284         186b         1,9-dioxo-15α-hydroxy-18,19,20-                                          trinor-17-                                                                     phenyl-1-hydroxymethyl-13-trans-prost                                          ene                                       728  320    284         186e         1,9-dioxo-15α-hydroxy-18,19,20-                                          trinor-17-                                                                     (m-trifluoromethylphenyl)-1-hydroxyme                                          th-                                                                            yl-13-trans-prostene                      729  320    284         186d         1,9-dioxo-15α-hydroxy-18,19,20-                                          trinor-17-                                                                     (p-methoxyphenyl)-1-hydroxymethyl-13-                                          3                                                                              trans-prostene                            730  319    285         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-1-hydroxy                                          methyl-2-                                                         ylmethoxy-1-trans-                                                                          nor-13-trans-prostadiene                                          octene (U.S. Pat.                                                              No. 3,873,607).                                        731  319    285         190          1,9-dioxo-15α-hydroxy-15-methyl                                          -1-hydroxy-                                                                    methyl-2-nor-13-trans-prostene            732  319    285         1-iodo-3-triphen-                                                                           1,9-dioxo-15α-hydroxy-16,16-dim                                          ethyl-1-hy-                                                       ylmethoxy-5,5-di-                                                                           droxymethyl-2-nor-13-trans-prostene                               methyl-octene (U.S.                                                            Pat. No. 3,873,607).                                   733  319    285         13           1,9-dioxo-15α-hydroxy-16,16-tri                                          methylene-                                                                     1-hydroxymethyl-2-nor-13-trans-proste                                          ne                                        734  319    285         76           erythro-1,9-dioxo-15α,16-dihydr                                          oxy-1-hy-                                                                      droxymethyl-2-nor-13-trans-prostene       735  319    285         69           threo-1,9-dioxo-15α,16-dihydrox                                          y-1-hydr-                                                                      oxymethyl-2-nor-13-trans-prostene         736  319    285         74           erythro-1,9-dioxo-15α-hydroxy-1                                          6-methoxy-                                                                     1-hydroxymethyl-2-nor-13-trans-proste                                          ne                                        737  319    285         107          1,9-dioxo-16-hydroxy-1-hydroxymethyl-                                          2-                                                                             nor-13-trans-prostene                     738  319    285         130          1,9-dioxo-16-hydroxy-16-methyl-1-hydr                                          oxy-                                                                           methyl-2-nor-13-trans-prostene            739  319    285         134          1,9-dioxo-16-hydroxy-16-methyl-1-hydr                                          oxy-                                                                           methyl-2-nor-13-trans-17-trans-prosta                                          diene                                     740  320    285         186          1,9-dioxo-15α-hydroxy-2,17,18,1                                          9,20-penta-                                                                    nor-16-phenoxy-1-hydroxymethyl-13-tra                                          ns-                                                                            prostene                                  741  320    285         180          1,9-dioxo-15α-hydroxy-2,17,18,1                                          9,20-penta-                                                                    nor-16-m-trifluoromethylphenoxy-1-hyd                                          roxy-                                                                          methyl-13-trans-prostene                  742  319    285         194          1,9-dioxo-16-hydroxy-16-vinyl-1-hydro                                          xy-                                                                            methyl-2-nor-13-trans-prostene            743  320    285         198          1,9-dioxo-16-hydroxy-16-cyclopropyl-1                                          -hy-                                                                           droxymethyl-2-nor-13-trans-prostene       744  320    285         186b         1,9-dioxo-15α-hydroxy-2,18,19,2                                          0-tetranor-                                                                    17-phenyl-1-hydroxymethyl-13-trans-pr                                          ost-                                                                           ene                                       745  319    285         186e         1,9-dioxo-15α-hydroxy-2,18,19,2                                          0-tetranor-                                                                    17-(m-trifluorophenyl)-1-hydroxymethy                                          l-                                                                             13-trans-prostene                         746  319    285          186d        1,9-dioxo-15α-hydroxy-2,18,19,2                                          0-tetranor-                                                                    17-(p-methoxyphenyl)-1-hydroxymethyl-                                          13-                                                                            trans-prostene                            __________________________________________________________________________

EXAMPLES 747-769

By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 39 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 39. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃ . . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      TABLE 38                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tine of                                                                             1,9-dioxo-1-hydroxymethylprostene and         Example                                                                             Example                                                                              of Example Example    its diastereomer                              __________________________________________________________________________     747  319   284        246        nat-(and ent)-1,9-dioxo-15-hydroxy-15-                                         16-tetramethylene-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene             748  320   284        245        nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                      N                                                                              tetramethylene-18,19,20-trinor-1-hydroxy-                                      O                                                                              methyl-13-trans-prostene                      749  319   284        243        nat-15S,16R(and ent-15R,16S)-1,9-dioxo-15                                      -                                                                              hydroxy-15,16-trimethylene-1-hydroxymeth-                                      g                                                                              yl-13-trans-prostene                          750  319   284        243        nat-15S,16R)and ent-15R,16S)-1,9-dioxo-                                        15-hydroxy-15,16-trimethylene-1-hydroxy-                                       r                                                                              methyl-13-trans-prostene                      751  319   284        251        nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       u                                                                              15-hydroxy-15,16-trimethylene-1-hydroxy-                                       e                                                                              methyl-13-trans-prostene                      752  319   284        247        nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      n                                                                              trimethylene-17,18,19,20-tetranor-1-hy-                                        droxymethyl-13-trans-prostene                 753  320   284        248        nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      t                                                                              pentamethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene               754  319   284        249        nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       .                                                                              15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-prostene                      755  319   284        250        nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       Z                                                                              15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-prostene                      756  319   284        252        nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       2                                                                              15-hydroxy-15,16-tetramethylene-1-                                             hydroxymethyl-13-trans-prostene               757  319   284        253        nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       6                                                                              15-hydroxy-15,16-tetramethylene-1-                                             hydroxymethyl-13-trans-prostene               758  320   284        254        nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       .                                                                              15,-hydroxy-15,16-trimethylene-16-(3-tri-                                      a                                                                              fluoromethylphenoxy)-17,18,19,20-tetra-                                        nor-1hydroxymethyl-13-trans-prostene          759  320   284        255        nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       p                                                                              15-hydroxy-15,16-trimethylene-16-(3-tri-                                       p                                                                              fluoromethylphenoxy)-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-prostene         760  319   284        256        nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       r                                                                              15-hydroxy-15,16-trimethylene-16-(4-                                           fluorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene               761  319   284        257        nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       x                                                                              15-hydroxy-15,16-trimethylene-16-(4-fluo-                                      e                                                                              rophenoxy)-17,18,19,20-tetranor-1-                                             hydroxymethyl-13-trans-prostene               762  320   284        258        nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       q                                                                              15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene               763  320   284        259        nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       .                                                                              15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene               764  319   284        260        nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       Z                                                                              15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-prostene         765  319   284        261        nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       2                                                                              15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-prostene         766  320   284        262        nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       7                                                                              16-hydroxy-16,17-trimethylene-20-meth-                                         yl-1-hydroxymethyl-13-trans-prostene          767  320   284        263        nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       .                                                                              16-hydroxy-16,17-trimethylene-20-meth-                                         yl-1-hydroxymethyl-13-trans-prostene          768  320   284        264        nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       c                                                                              16-hydroxy-16,17-trimethylene-16-(3-tri-                                       e                                                                              fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-prostene               769  320   284        265        nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       n                                                                              16-hydroxy-16,17-trimethylene-16-(3-tri-                                       t                                                                              fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-prostene               __________________________________________________________________________

EXAMPLE 770 Preparation of l-9-oxo-15(S)-acetoxy prostanoyl chloride

To a solution of 0.5 g of l-9-oxo-15(S)-acetoxy prostanoic acid in 10 ml of benzene at 0° C. with stirring is added 0.5 ml of oxalyl chloride. The mixture is stirred at room temperature for 21/2 hours. The solvent and excess oxalyl chloride is removed at reduced pressure. The residue is dissolved in hexane and filtered. The solvent is removed giving the title compound.

EXAMPLE 771 Preparation of l-1,9-dioxo-15(S)-acetoxy-1-hydroxymethyl-prostene

To a solution of 11.9 mmol of diazomethane in ether at 0° C. with stirring is added dropwise a solution of 2.99 mmol of l-9-oxo-15(S)-acetoxy prostanoyl chloride (Example 770) in 10 ml of ether. After 10 minutes the solution is warmed to room temperature and the solvent and excess diazomethane is removed in a stream of nitrogen. The residue is stirred at 55° C. in 15 ml of tetrahydrofuran containing 5.75 ml of 2 M sulfuric acid for 30 minutes. The mixture is poured into water and extracted with ether. The ether solution is washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The ether is removed and the residue is chromatographed on a dry column of silica gel eluting with hexane-ethyl acetate 3:2 to give the title compound.

EXAMPLE 772 Preparation of l-1,9-dioxo-15(S)-hydroxy-1-hydroxymethyl prostane

A solution of 0.41 g of l-1,9-dioxo-15(S)-acetoxy-1-hydroxymethyl prostane (Example 771) in 8 ml of methanol containing 1 ml of water and 0.19 ml of concentrated sulfuric acid is refluxed for 5 hours. The methanol is removed at reduced pressure and water and tetrahydrofuran is added. The mixture is then refluxed for 1 hour. The mixture is poured into dilute sodium bicarbonate and extracted with ether. The ether solution is washed with brine and dried over magnesium sulfate. The solvent is removed giving 0.34 g of the title compound.

EXAMPLE 773 Preparation of 1,9-dioxy-11α,16-dihydroxy-1-hydroxymethyl-20-nor-5-cis-13-trans-prostadiene, 1-ethylene ketal

To a solution of 3.58 g (7.0 mmol) of 1-iodo-4-triphenylmethoxy-1-trans-nonene 112) 112) in 8.0 ml of ether is added 8.9 ml of 1.6 M t-butyllithium solution (14.1 mmol) with stirring under argon at -78° C. The solution is allowed to warm to -30° C. over a 2 hour period. The solution is recooled to -78° C. and a solution of 7.0 mmol of copper pentyne and 2.9 ml of hexamethylphosphorous triamide in 20 ml of ether is added. After 1 hour, 3.28 g (7.0 mmol) of 2-(8-dimethyl-t-butylsilyloxy-7-oxooct-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one, 7-ethylene ketal (Example 280) in 5 ml of ether is added. The mixture is stirred at -30° C. for 2 hours and at 0° C. for 30 minutes. The mixture is poured into 150 ml of saturated ammonium chloride and extracted with ether. The ether solution is washed with dilute hydrochloric acid and dried over magnesium sulfate to give 6.0 g of an oil. A 3.0 g portion of this oil is stirred in 40 ml of tetrahydrofuran-0.6 N Hydrochloric acid 5:1 for 5 hours at room temperature.

The mixture is poured into water and extracted with ether. The ether is removed and the residue is heated in 70 ml of acetic acid-tetrahydrofuran-water 4:2:1 at 60° C. for 4 hours. The solvent is removed at reduced pressure. Toluene is added and removed. The residue is chromatographed on a silica gel column eluting with ethyl acetate giving 0.1 g of the title compound.

EXAMPLE 774 Preparation of 1,9-dioxo-11α,16-dihydroxy-16-methyl-1-hydroxymethyl-5-cis-13-trans-prostadiene, 1-ethylene ketal

To a solution of 3.4 g (6.75 mmol) of (E)-4-trimethylsilyloxy-4-methyl-1-tri-n-butylstannyloctene (Example 210b) in 3.5 ml of tetrahydrofuran with stirring at -78° C. under argon is added 2.8 ml (6.75 mmol) of 2.4 M n-butyllithium in hexane. The solution is maintained at -20° to -15° C. for 21/2 hours. A solution of 0.89 g (6.75 mmol) of copper pentyne and 2.2 g of hexamethylphosphorous triamide in 25 ml of ether is added at -78° C. After 1 hour, a solution of 2.3 g (5.0 mmol) of 2-(8-dimethyl-t-butylsilyloxy-7-oxooct-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one, 7-ethylene ketal (Example 280) in 20 ml of ether is added. The solution is stirred at -45° C. for 30 minutes and at -45° to -20° C. over 30 minutes. To the solution is added 3 ml of acetic acid followed by saturated ammonium chloride. The mixture is poured into water and extracted with ether. The ether solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is stirred in 75 ml of tetrahydrofuran containing 15 ml of 0.6 N hydrochloric acid and 1 ml of acetic acid at room temperature for 5 hours. The solution is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ethyl acetate containing 0.5% acetic acid (1000 ml) to give 0.65 g of the title compound.

EXAMPLES 776-868

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 40 are prepared by the indicated method from the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 40; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomers are also formed and are part of this invention.

                                      TABLE 40                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example   1,9-dioxo-1-hydroxymethylprostene              __________________________________________________________________________     775  773   280         49       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     -                                                                              methyl-16,16-trimethylene-20-nor-5-cis-                                        13-trans-prostadiene,1-ethylene ketal          776  773   280         50       1,9-dioxo-11α,15 -dihydroxy-1-hydrox                                     y-                                                                             methyl-16,16-trimethylene-20-methyl-5-                                         cis-13-trans-prostadiene,1-ethylene                                            ketal                                          777  773   280         51       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16,16-trimethylene-20-ethyl-5-cis-13-                                       trans-prostadiene,1-ethylene ketal             778  773   280         13       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16,16-trimethylene-13-trans-5-cis-                                          prostadiene,1-ethylene ketal                   779  774   280         210a     1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-16-vinyl-5-cis-13-trans-prostadiene,1-                                      8                                                                              ethylene ketal                                 780  774   280        199       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     ropyl-                                                                         20-ethyl-1-hydroxymethyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                   781  774   280        201       1,9-dioxo-11α,16-ddihydroxy-16-vinyl                                     -20-                                                                           ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   782  774   280        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     ropyl-                                                                         1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                            783a                                                                               773   280         74       dl-erythro-1,9-dioxo-11α,15-dihydrox                                     y-16-                                                                          methoxy-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                    783b                                                                               774   280         210c     1,9-dioxo-11α ,16-dihydroxy-16-ethyl                                     -1-hy-                                                                         droxymethyl-5-cis-13-trans-prostadiene,1-                                      f                                                                              ethylene ketal                                 784  773   280         77       dl-erythro-1,9-dioxo-11α,15-dihydrox                                     y-                                                                             16-ethoxy-1-hydroxymethyl-5-cis-13-                                            trans-prostadiene,1-ethylene ketal             785  773   280         83       dl-erythro-1,9-dioxo-11α,15,16-trihy                                     dr-                                                                            oxy-1-hydroxymethyl-20-nor-5-cis-13-                                           trans-prostadiene,1-ethylene ketal             786  773   280         84       dl-erythro-1,9-dioxo-11α,15,16-trihy                                     dr-                                                                            oxy-20-methyl-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene,1-ethylene ketal             787  773   280         85       dl-erythro-1,9-dioxo-11α,15,16-trihy                                     dr-                                                                            oxy-20-ethyl-1-hydroxymethyl-5-cis-13-                                         trans-prostadiene,1-ethylene ketal             788  773   280         86       dl-erythro-1,9-dioxo-11α,15,16-trihy                                     dr-                                                                            oxy-19-methyl-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene,1-ethylene ketal             789  773   280         87       dl-erythro-1,9-dioxo-11α,15,16-trihy                                     dr-                                                                            oxy-1-hydroxymethyl-5-cis-13-trans-17-                                         trans-prostatriene,1-ethylene ketal            790  773   280         69       di-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           1-hydroxymethyl-5-cis-13-trans-hydroxy-                                        methyl,1-ethylene ketal                        791  773   280         88       dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           20-nor-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                   792  773   280         76       dl-erythro-1,9-dioxo-11α,15,16-trihy                                     droxy-                                                                         1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           793  773   280         89       dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           20-methyl-1-hydroxymethyl-5-cis-13-                                            trans-prostadiene,1-ethylene ketal             794  773   280          90      dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           20-ethyl-1-hydroxymethyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                   795  773   280         91       dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oxy-                                                                           19-methyl-1-hydroxymethyl-5-cis-13-                                            trans-prostadiene,1-ethylene ketal             796  773   280         92       dl-threo-1,9-dioxo-11α,15,16-trihydr                                     oyxy-                                                                          1-hydroxymethyl-5-cis-13-trans-17-trans-                                       prostatriene,1-ethylene ketal                  797  773   280        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-5-cis-13-trans-prostadiene,1-ethylene                                       ketal                                          798  773   280        108       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-19,20-dinor-5-cis-13-trans-prostadiene,                                     3                                                                              1-ethylene ketal                               799  773   280        109       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-18,19,20-trinor-5-cis-13-trans-prosta-                                      +                                                                              diene,1-ethylene ketal                         800  773   280        110       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-20-nor-5-cis-13-trans-prostadiene,1-                                        ethylene ketal                                 801  773   280        144       1,9-dioxo-11α,16-dihydroxy-17-methyl                                     -1-                                                                            hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           802  773   280        112       1,9-dioxo-11α,16-dihydroxy-20-methyl                                     -1-                                                                            hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           803  773   280        113       1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                     1-                                                                             hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           804  773   280         139a     1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -20-                                                                           ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   805  773   280        115       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-13-trans-17-cis-5-cis-prostatriene,1-                                       ethylene ketal                                 806  773   280        135       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           807  773   280        136       1,9-dioxo-11α,16-dihydroxy-17,17,20-                                     tri-                                                                           methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                   808  773   280        137       1,9-dioxo-11α,16-dihydroxy-16,20-dim                                     eth-                                                                           yl-1-hydroxymethyl-13-trans-5-cis-prosta-                                      =                                                                              diene,1-ethylene ketal                         809  773   280        138       1,9-dioxo-11α,16-dihydroxy-17,17-dim                                     eth-                                                                           yl-1-hydroxymethyl-5-cis-13-trans-prost-                                       adiene,1-ethylene ketal                        810  773   280        139       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-13-trans-17-trans-5-cis-                                         prostatriene,1-ethylene ketal                  811  773   280        149       1,9-dioxo-11α,16-dihydroxy-20-methyl                                     -1-                                                                            hydroxymethyl-13-trans-17-trans-5-cis-                                         prostratriene,1-ethylene ketal                 812  773   280        150       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           813  773   280        151       1,9-dioxo-11α,16-dihydroxy-17,20-dim                                     eth-                                                                           yl-1-hydroxymethyl-5-cis-13-trans-prosta-                                      i                                                                              diene,1-ethylene ketal                         814  773   280        152       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-13-trans-17-trans-5-cis-prostatriene,-                                      e                                                                              1-ethylene ketal                               815  773   280        153       1,9-dioxo-11α,16(R)-dihydroxy-1-hydr                                     oxy-                                                                           methyl-5-cis-13-trans-prostadiene,1-eth-                                       ylene ketal                                    816  773   280        154       1,9-dioxo-11α,16(S)-dihydroxy-1-hydr                                     oxy-                                                                           methyl-5-cis-13-trans-prostadiene,1-eth-                                       ylene ketal                                    817  773   280         148a     1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                     1-                                                                             hydroxymethyl-5-cis-13-trans-17-trans-                                         prostatriene,1-ethylene ketal                  818  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-1-                                     hydroxymeth-                                                         ylmethoxy-1-trans-                                                                       yl-5-cis-13-trans-prostadiene,1-ethylene                             octene (U.S. Pat.                                                                        ketal                                                                No. 3,873,607).                                          819  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-20                                     -methyl-1-                                                           ylmethoxy-1-trans-                                                                       hydroxymethyl-5-cis-13-trans-prostadiene                             nonene (U.S. Pat.                                                                        1-ethylene ketal                                                     No. 3,873,607).                                          820  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-20                                     -ethyl-1-                                                            ylmethoxy-1-trans-                                                                       hydroxymethyl-5-cis-13-trans-prostadiene,                                      d                                                                    decene (U.S. Pat.                                                                        1-ethylene ketal                                                     No. 3,873,607).                                          821  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-dimeth-                                                          ylmethoxy-4,4-di-                                                                        yl-1-hydroxymethyl-5-cis-13-trans-prosta-                                      v                                                                    methyl-1-trans-                                                                          diene,1-ethylene ketal                                               octene (U.S. Pat.                                                              No. 3,873,607).                                          822  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-17                                     ,17-dimeth-                                                          ylmethoxy-5,5-di-                                                                        yl-5-cis-13-trans-prostadiene,1-ethylene                             methyl-1-trans-                                                                          ketal                                                                octene (U.S. Pat.                                                              No. 3,873,607).                                          823  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-16                                     -methyl-1-                                                           ylmethoxy-4-meth-                                                                        hydroxymethyl-5-cis-13-trans-prostadiene,                                      3                                                                    yl-1-trans-octene                                                                        1-ethylene ketal                                                     (U.S. Pat. No.                                                                 3,876,690).                                              824  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-16                                     -ethyl-1-                                                            ylmethoxy-4-ethyl-                                                                       hydroxymethyl-5-cis-13-trans-prostadiene,                                      .                                                                    1-trans-octene                                                                           1-ethylene ketal                                                     (U.S. Pat. No.                                                                 3,876,690).                                              825  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-17                                     ,20-tetra-                                                           ylmethoxy-3-cyclo-                                                                       nor-16-cyclopentyl-1-hydroxymethyl-5-cis-                                      -                                                                    pentyl-1-trans-                                                                          13-trans-prostadiene,1-ethylene ketal                                butene (U.S. Pat.                                                              No. 3,884,969).                                          826  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-16                                     ,20-penta-                                                           ylmethoxy-3-cyclo-                                                                       nor-15-cyclohexyl-1-hydroxymethyl-5-cis-                             hexyl-1-trans-                                                                           13-trans-prostadiene,1-ethylene ketal                                pentene (U.S. Pat.                                                             No. 3,884,969).                                          827  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-18                                     ,20-trinor-                                                          ylmethoxy-5-cyclo-                                                                       17-cyclohexyl-1-hydroxymethyl-5-cis-13-                              hexyl-1-trans-                                                                           trans-prostadiene,1-ethylene ketal                                   pentene (U.S. Pat.                                                             No. 3,884,969).                                          828  773   280        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-19                                     ,20-dinor-                                                           ylmethoxy-6-cyclo-                                                                       18-cyclopentyl-1-hydroxymethyl-5-cis-13-                             pentyl-1-trans-                                                                          trans-prostadiene,1-ethylene ketal                                   hexene (U.S. Pat.                                                              No. 3,884,969).                                          829  773   280        1-iodo-3-methyl-3-                                                                       1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-1-                                                           trimethylsilyl-                                                                          hydroxymethyl-5-cis-13-trans-prostadiene,                                      3                                                                    oxy-trans-1-octene                                                                       1-ethylene ketal                                                     (Example 125)                                            830  773   280        1-iodo-3-methyl-3-                                                                       1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-20-                                                          trimethylsilyl                                                                           ethyl-1-hydroxymethyl-5-cis-13-trans-                                oxy-trans-1-decene                                                                       prostadiene,1-ethylene ketal                                         (Example 190a)                                           831  774   280        159       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-fluorophenoxy-1-hydroxy-                                         methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     -                                                                              ene ketal                                      832  774   280        186       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-phenoxy-1-hydroxymethyl-5-                                         cis-13-trans-prostadiene,1-ethylene                                            ketal                                          833  774   280        181       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-bromophenoxy-1-hydroxy-                                          methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     Z                                                                              ene ketal                                      834  774   280        182       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-t-butylphenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     7                                                                              ene ketal                                      835  774   280        183       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-methoxyphenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     u                                                                              ene ketal                                      836  774   280        184       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-p-chlorophenoxy-1-hydroxy-                                         methyl-5-cis-13-trans-prostadiene,1-                                           ethylene ketal                                 837  774   280        180       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-m-trifluorophenoxy-1-hydroxy-                                         methyl-5-cis-13-trans-prostadiene,1-                                           ethylene ketal                                 838  774   280        185       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-(3,4-dichlorophenoxy)-1-hy-                                        droxymethyl-5-cis-13-trans-prostadiene,1-                                      Z                                                                              ethylene ketal                                 839  774   280         186b     1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-tri-                                                                    nor-17-phenyl-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene,1-ethylene ketal             840  774   280         186e     1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-tri-                                                                    nor-17-(m-trifluoromethylphenyl)-1-hydr-                                       oxymethyl-5-cis-13-trans-prostadiene,1-                                        ethylene ketal                                 841  774   280         186d     1,9-dioxo-11α,15α-dihydroxy-18                                     ,19,20-tri-                                                                    nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                      u                                                                              5-cis-13-trans-prostadiene,1-ethylene                                          ketal                                          842  773   297        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-1-                                     hydroxymeth-                                                         ylmethoxy-1-trans-                                                                       yl-2-nor-5-cis-13-trans-prostadiene,1-                               octene (U.S. Pat.                                                                        ethylene ketal                                                       No. 3,873,607).                                          843  773   297        185       1,9-dioxo-11α,15α-dihydroxy-15                                     -methyl-1-                                                                     hydroxymethyl-2-nor-5-cis-13-trans-prost-                                      e                                                                              adiene,1-ethylene ketal                        844  773   297        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-dimeth-                                                          ylmethoxy-5,5-di-                                                                        yl-1-hydroxymethyl-2-nor-5-cis-13-trans-                             methyl octene                                                                            prostadiene,1-ethylene ketal                                         (U.S. Pat. No.                                                                 3,873,607).                                              845  773   297         13       1,9-dioxo-11α,15α-dihydroxy-16                                     ,16-tri-                                                                       methylene-1-hydroxymethyl-2-nor-5-cis-                                         13-trans-prostadiene,1-ethylene ketal          846  773   297         76       erythro-1,9-dioxo-11α,15α,16-t                                     rihydroxy                                                                      1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   847  773   297         69       threo-1,9-dioxo-11α,15α,16-tri                                     hydroxy-1-                                                                     hydroxymethyl-2-nor-5-cis-13-trans-                                            prostadiene,1-ethylene ketal                   848  773   297         74       erythro-1,9-dioxo-11α,15α,16-d                                     ihydroxy-16-                                                                   methoxy-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                   849  773   297        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                     meth-                                                                          yl-2-nor-5-cis-13-trans-prostadiene,1-                                         ethylene ketal                                 850  773   297        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-2-nor-5-cis-13-trans-                                            prostadiene,1-ethylene ketal                   851  773   297        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            hydroxymethyl-2-nor-5-cis-13-trans-17-                                         trans-prostadiene,1-ethylene ketal             852  774   297        186       1,9-dioxo-11α,15α-dihydroxy-2,                                     17,18,19,-                                                                     20-pentanor-16-phenoxy-1-hydroxymethyl-5-                                      r                                                                              cis-13-trans-prostadiene,1-ethylene                                            ketal                                          853  774   297        180       1,9-dioxo-11α,15α-dihydroxy-2,                                     17,18,19,-                                                                     20-pentanor-16-m-trifluoromethylphenoxy-                                       1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           854  773   297        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-hy-                                                                          droxymethyl-2-nor-5-cis-13-trans-prosta-                                       diene,1-ethylene ketal                         855  774   297        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     ropyl-                                                                         1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   856  774   297         186b     1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,20-                                                                      tetranor-17-phenyl-1-hydroxymethyl-5-                                          cis-13-trans-prostadiene,1-ethylene                                            ketal                                          857  773   297         186e     1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,20-                                                                      tetranor-17-(m-trifluorophenyl)-1-hydr-                                        oxymethyl-5-cis-13-trans-prostadiene,1-                                        ethylene ketal                                 858  773   297         186d     1,9-dioxo-11α,15α-dihydroxy-2,                                     18,19,20-                                                                      tetranor-17-(p-methoxyphenyl)-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     n                                                                              ene ketal                                      859  773   310        125       1,9-dioxo-15-hydroxy-15-methyl-1-hydroxy-                                      .                                                                              methyl-2-nor-13-trans-prostene,1-ethylene                                      Z                                                                              ketal                                          860  773   298        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            homo-1-hydroxymethyl-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                   861  773   298        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                     -1-                                                                            homo-1-hydroxymethyl-5-cis-13-trans-17-                                        trans-prostatriene,1-ethylene ketal            862  774   298        186       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-phenoxy-1-hydroxymethyl-5-                                         cis-13-trans-prostadiene,1-ethylene                                            ketal                                          863  774   298        180       1,9-dioxo-11α,15α-dihydroxy-17                                     ,18,19,20-                                                                     tetranor-16-m-trifluoromethylphenoxy-1-                                        hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           864  773   298        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                     1-homo-                                                                        1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           865  774   298        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                     rop-                                                                           yl-1-homo-1-hydroxymethyl-5-cis-13-trans-                                      q                                                                              prostadiene,1-ethylene ketal                   866  774   298         186b     1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-18,19,-                                                                   20-trinor-17-phenyl-1-hydroxymethyl-5-cis-                                     o                                                                              13-trans-prostadiene,1-ethylene ketal          867  773   298         186e     1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-18,19,-                                                                   20-trinor-17-(m-trifluorophenyl)-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene,1-                                        ethylene ketal                                 868  773   298         186d     1,9-dioxo-11α,15α-dihydroxy-1-                                     homo-18,19,-                                                                   20-trinor-17-(p-methoxyphenyl)-1-hydroxy-                                      Z                                                                              methyl-13-trans-5-cis-prostadiene,1-ethyl-                                     4                                                                              ene ketal                                      __________________________________________________________________________

EXAMPLES 869-891

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 41 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 41. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃. . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      TABLE 41                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tin of                                                                           1,9-dioxo-1-hydroxymethylprostene and            Example                                                                             Example                                                                              of Example Example its diastereomer                                 __________________________________________________________________________     869  773   280        246     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-tetramethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-5-cis-13-trans-                                            prostadiene,1-ethylene ketal                     870  774   280        245     nat-(and ent)-1,9-dioxo-11α,16-dihydro                                   xy-                                                                            16,17-tetramethylene-18,19,20-trinor-1-                                        hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                             871  773   280        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   2                                                                              hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                             872  773   280        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   .                                                                              hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             873  773   280        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α, 15-dihydroxy-15,16-trimethylene-1                                   -                                                                              hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             874  773   280        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-trimethylene-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                             875  774   280        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-pentamethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-5-cis-prosta-                                     diene,1-ethylene ketal                           876  773   280        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-h                                   y-                                                                             droxymethyl-13-trans-5-cis-prostadiene,1-                                      ethylene ketal                                   877  773   280        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-h                                   y-                                                                             droxymethyl-13-trans-5-cis-prostadiene,1-                                      ethylene ketal                                   878  773   280        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   1-                                                                             hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             879  773   280        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   1-                                                                             hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             880  774   280        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene,1-ethylene ketal                     881  774   280        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene,1-ethylene ketal                     882  773   280        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α, 15-dihydroxy-15,16-trimethylene-1                                   6-                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                             883  773   280        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-1-                                      hydroxymethyl-13-trans-13-5-cis-prostadi-                                      ene,1-ethylene ketal                             884  774   280        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                             885  774   280        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                             886  773   280        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene,1-ethylene ketal                     887  773   280        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-trans-5-cis-                                       prostadiene,1-ethylene ketal                     888  774   280        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-20                                   -                                                                              methyl-1-hydroxymethyl-13-trans-5-cis-                                         prostadiene,1-ethylene ketal                     889  774   280        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-20                                   -                                                                              methyl-1-hydroxymethyl-13-trans-5-cis-                                         prostadiene,1-ethylene ketal                     890  774   280        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylpenoxy)-18,19,20-tri-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene,1-ethylene ketal                          891  774   280        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-                                           nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene,1-ethylene ketal                          __________________________________________________________________________

EXAMPLES 892-975

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-hydroxymethyl prostene derivatives shown in Table 42 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 42; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 42                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example  1,9-dioxo-1-hydroxymethylprostene               __________________________________________________________________________     892  773   309        49       1,9-dioxo-11α,15-dihydroxy-1-hydroxym                                    eth-                                                                           yl-16,16-trimethylene-20-nor-13-trans-                                         prostene,1-ethylene ketal                       893  773   309        50       1,9-dioxo-11α,15-dihydroxy-1-hydroxym                                    eth-                                                                           yl-16,16-trimethylene-20-methyl-13-trans-                                      prostene,1-ethylene ketal                       894  773   309        51       1,9-dioxo-11α,15-dihydroxy-1-hydroxym                                    eth-                                                                           yl-16,16-trimethylene-20-ethyl-13-trans-                                       prostene,1-ethylene ketal                       895  774   309        193      1,9-dioxo-11α,16-dihydroxy-16-cyclopr                                    op-                                                                            yl-20-ethyl-1-hydroxymethyl-13-trans-                                          prostene,1-ethylene ketal                       896  774   309        195      1,9-dioxo-11α,16-dihydroxy-16-vinyl-2                                    0-                                                                             ethyl-1-hydroxymethyl-13-trans-prostene,                                       1-ethylene ketal                                897  774   309        192      1,9-dioxo-11α,16-dihydroxy-16-cyclopr                                    op-                                                                            yl-1-hydroxymethyl-13-trans-prostene,1-                                        ethylene ketal                                  898  773   309        13       1,9-dioxo-11α,15-dihydroxy-1-hydroxym                                    eth-                                                                           yl-16,16-trimethylene-13-trans-prostene,                                       1-ethylene ketal                                899  773   309        210a     1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-16-vinyl-13-trans-prostene,1-ethylene                                       ketal                                           900  773   309        74       dl-erythro-1,9-dioxo-11α,15-dihydroxy                                    -16-                                                                           methoxy-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                            901  773   309        77       dl-erythro-1,9-dioxo-11α,15-dihydroxy                                    -16-                                                                           ethoxy-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                            902  773   309        83       dl-erythro-1,9-dioxo-11α,15,16-trihyd                                    r-                                                                             oxy-1-hydroxymethyl-20-nor-13-trans-                                           prostene,1-ethylene ketal                       903  773   309        84       dl-erythro-1,9-dioxo-11α,15,16-trihyd                                    r-                                                                             oxy-1-hydroxymethyl-20-methyl-13-trans-                                        prostene,1-ethylene ketal                       904  773   309        85       dl-erythro-1,9-dioxo-11α,15,16-trihyd                                    r-                                                                             oxy-1-hydroxymethyl-20-ethyl-13-trans-                                         prostene,1-ethylene ketal                       905  773   309        86       dl-erythro-1,9-dioxo-11α,15,16-trihyd                                    r-                                                                             oxy-19-methyl-1-hydroxymethyl-13-trans-                                        prostene,1-ethylene ketal                       906  773   309        87       dl-erythro-1,9-dioxo-11α,15,16-trihyd                                    r-                                                                             oxy-13-trans-17-trans-prostadiene,1-eth-                                       ylene ketal                                     907  773   309        69       dl-threo-1,9-dioxo-11α,15,16-trihydro                                    xy-                                                                            1-hydroxymethyl-13-trans-prostene,1-                                           ethylene ketal                                  908  773   309        88       dl-threo-1,9-dioxo-11α,15,16-trihydro                                    xy-                                                                            20-nor-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                            909  773   309        76       dl-erythro-1,9-dioxo-11α,15,16-trihyd                                    r-                                                                             oxy-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                  910  773   309        89       dl-threo-1,9-dioxo-11α,15,16-trihydro                                    xy-                                                                            20-methyl-1-hydroxymethyl-13-trans-                                            prostene,1-ethylene ketal                       911  773   309        90       dl-threo-1,9-dioxo-11α,15,16-trihydro                                    xy-                                                                            20-ethyl-1-hydroxymethyl-13-trans-prost-                                       ene,1-ethylene ketal                            912  773   309        91       dl-threo-1,9-dioxo-11α,15,16-trihydro                                    xy-                                                                            19-methyl-1-hydroxymethyl-13-trans-                                            prostene,1-ethylene ketal                       913  773   309        92       dl-threo-1,9-dioxo-11α,15,16-trihydro                                    xy-                                                                            1-hydroxymethyl-13-trans-17-trans-                                             prostadiene,1-ethylene ketal                    914  773   309        107      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-13-trans-prostene,1-ethylene ketal           915  773   309        108      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-19,20-dinor-13-trans-prostene,1-ethyl-                                      ene ketal                                       916  773   309        109      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-18,19,20-trinor-13-trans-prostene,1-                                        ethylene ketal                                  917  773   309        110      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-20-nor-13-trans-prostene,1-ethylene                                         ketal                                           918  773   309        144      1,9-dioxo-11α,16-dihydroxy-17-methyl-                                    1-                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                       919  773   309        112      1,9-dioxo-11α,16-dihydroxy-20-methyl-                                    1-                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                       920  773   309        113      1,9-dioxo-11α,16-dihydroxy-20-ethyl-1                                    -                                                                              hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                       921  773   309        139a     1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    20-                                                                            ethyl-1-hydroxymethyl-13-trans-prostene,                                       1-ethylene ketal                                922  773   309        115      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-13-trans-17-cis-prostadiene,1-ethylene                                      ketal                                           923  773   309        135      1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    1-                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                       924  773   309        136      1,9-dioxo-11α,16-dihydroxy-17,17,20-t                                    ri-                                                                            methyl-1-hydroxymethyl-13-trans-prostene,                                      1-ethylene ketal                                925  773   309        137      1,9-dioxo-11α,16-dihydroxy-16,20-dime                                    th-                                                                            yl-1-hydroxymethyl-13-trans-prostene,1-                                        ethylene ketal                                  926  773   309        138      1,9-dioxo-11α,16-dihydroxy-17,17-dime                                    th-                                                                            yl-1-hydroxymethyl-13-trans-prostene,1-                                        ethylene ketal                                  927  773   309        139      1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    1-                                                                             hydroxymethyl-13-trans-17-trans-prosta-                                        diene,1-ethylene ketal                          928  773   309        149      1,9-dioxo-11α,16-dihydroxy-20-methyl-                                    1-                                                                             hydroxymethyl-13-trans-17-trans-prosta-                                        diene,1-ethylene ketal                          929  773   309        150      1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    1-                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                       930  773   309        151      1,9-dioxo-11α,16-dihydroxy-17,20-dime                                    th-                                                                            yl-1-hydroxymethyl-13-trans-prostene,1-                                        ethylene ketal                                  931  773   309        152      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-13-trans-17-trans-prostadiene,1-ethyl-                                      ene ketal                                       932  773   309        153      1,9-dioxo-11α,16(R)-dihydroxy-1-hydro                                    xy-                                                                            methyl-13-trans-prostene,1-ethylene ketal       933  773   309        154      1,9-dioxo-11α,16(S)-dihydroxy-1-hydro                                    xy-                                                                            methyl-13-trans-prostene,1-ethylene ketal       934  773   309        148a     1,9-dioxo-11α,16-dihydroxy-20-ethyl-1                                    -hy-                                                                           droxymethyl-13-trans-17-trans-prostadi-                                        ene,1-ethylene ketal                            935  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-1-h                                    ydroxy-                                                               ylmethoxy-1-trans-                                                                      methyl-13-trans-prostadiene,1-ethylene                                octene (U.S. Pat.                                                                       ketal                                                                 No. 3,873,607).                                          936  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-20-                                    methyl-1-                                                             ylmethoxy-1-trans-                                                                      hydroxymethyl-13-trans-prostene,1-ethyl-                              nonene (U.S. Pat.                                                                       ene ketal                                                             No. 3,873,607).                                          937  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α                                                  -dihydroxy-20-ethyl-1-                                                ylmethoxy-1-trans-                                                                      hydroxymethyl-13-trans-prostene,1-ethyl-                              decene (U.S. Pat.                                                                       ene ketal                                                             No. 3,873,607).                                          938  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16,                                    16-dimeth-                                                            ylmethoxy-4,4-di-                                                                       yl-1-hydroxymethyl-13-trans-prostene,1-                               methyl-1-trans-                                                                         ethylene ketal                                                        octene (U.S. Pat.                                                              No. 3,873,607).                                          939  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-17,                                    17-dimeth-                                                            ylmethoxy-5,5-di-                                                                       yl-1-hydroxymethyl-13-trans-prostene,1-                               methyl-1-trans-                                                                         ethylene ketal                                                        octene (U.S. Pat.                                                              No. 3,873,607).                                          940  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16-                                    methyl-1-                                                             ylmethoxy-4-meth-                                                                       hydroxymethyl-13-trans-prostene,1-ethyl-                              yl-1-trans-octene                                                                       ene ketal                                                             (U.S. Pat. No.                                                                 3,876,690).                                              941  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16-                                    ethyl-1-                                                              ylmethoxy-4-ethyl-                                                                      hydroxymethyl-13-trans-prostene,1-ethyl-                              1-trans-octene                                                                          ene ketal                                                             (U.S. Pat. No.                                                                 3,876,690).                                              942  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-17,                                    20-tetra-                                                             ylmethoxy-4-cyclo-                                                                      nor-16-cyclopentyl-1-hydroxymethyl-13-                                pentyl-1-trans-                                                                         trans-prostene,1-ethylene ketal                                       butene (U.S. Pat.                                                              No. 3,884,969).                                          943  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16,                                    20-penta-                                                             ylmethoxy-3-cyclo-                                                                      nor-15-cyclohexyl-1-hydroxymethyl-13-                                 hexyl-1-trans-                                                                          trans-prostene,1-ethylene ketal                                       pentene (U.S. Pat.                                                             No. 3,884,969).                                          944  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-18,                                    20-trinor-                                                            ylmethoxy-5-cyclo-                                                                      17-cyclohexyl-1-hydroxymethyl-13-trans-                               hexyl-1-trans-                                                                          prostene,1-ethylene ketal                                             pentene (U.S. Pat.                                                             No. 3,884,969).                                          945  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-19,                                    20-dinor-                                                             ylmethoxy-6-cyclo-                                                                      18-cyclopentyl-1-hydroxymethyl-13-trans-                              pentyl-1-trans-                                                                         prostene,1-ethylene ketal                                             hexene (U.S. Pat.                                                              No. 3,884,969).                                          946  773   309        1-iodo-3-methyl-                                                                        1,9-dioxo-11α,15α-dihydroxy-15-                                    methyl-1-                                                             3-trimethylsilyl-                                                                       hydroxymethyl-13-trans-prostene,1-ethyl-                              oxy-trans-1-octene                                                                      ene ketal                                                             (Example 125)                                            947  773   309        1-iodo-3-methyl-                                                                        1,9-dioxo-11α,15α-dihydroxy-15-                                    methyl-20-                                                            3-trimethylsilyl-                                                                       ethyl-1-hydroxymethyl-13-trans-prostene,                              oxy-trans-1-decene                                                                      1-ethylene ketal                                                      (Example 190a)                                           948  774   309        159      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-p-fluorophenoxy-1-hydroxy-                                         methyl-13-trans-prostene,1-ethylene ketal       949  774   309        186      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-phenoxy-1-hydroxymethyl-13-                                        trans-prostene,1-ethylene ketal                 950  774   309        181      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-p-bromophenoxy-1-hydroxy-                                          methyl-13-trans-prostene,1-ethylene ketal       951  774   309        182      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-p-t-butylphenoxy-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene ketal       952  774   309        183      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-p-methoxyphenoxy-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene ketal       953  774   309        184      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-p-chlorophenoxy-1-hydroxy-                                         methyl-13-trans-prostene,1-ethylene ketal       954  774   309        180      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-m-trifluorophenoxy-1-hydroxy-                                         methyl-13-trans-prostene,1-ethylene ketal       955  774   309        185      1,9-dioxo-11α,15α-dihydroxy-17,                                    18,19,20-                                                                      tetranor-16-(3,4-dichlorophenoxy)-1-hy-                                        droxymethyl-13-trans-prostene,1-ethylene                                       ketal                                           956  774   309        186b     1,9-dioxo-11α,15α-dihydroxy-18,                                    19,20-tri-                                                                     nor-17-phenyl-1-hydroxymethyl-13-trans-                                        prostene,1-ethylene ketal                       957  774   309        186e     1,9-dioxo-11α,15α-dihydroxy-18,                                    19,20-tri-                                                                     nor-17-(m-trifluoromethylphenyl)-1-hydro-                                      oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                           958  774   309        186d     1,9-dioxo-11α,15α-dihydroxy-18,                                    19,20-tri-                                                                     nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                      13-trans-prostene,1-ethylene ketal              959  773   312        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-1-h                                    ydroxy-                                                               ylmethoxy-1-trans-                                                                      methyl-2-nor-13-trans-prostadiene,1-                                  octene (U.S. Pat.                                                                       ethylene ketal                                                        No. 3,873,607).                                          960  773   312        185      1,9-dioxo-11α,15α-dihydroxy-15-                                    methyl-1-                                                                      hydroxymethyl-2-nor-13-trans-prostene,1-                                       ethylene ketal                                  961  773   312        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16,                                    16-dimeth-                                                            ylmethoxy-5,5-di-                                                                       yl-1-hydroxymethyl-2-nor-13-trans-prost-                              methyl-octene                                                                           ene,1-ethylene ketal                                                  (U.S. Pat. No.                                                                 3,873,607).                                              962  773   312        13       1,9-dioxo-11α,15α-dihydroxy-16,                                    16-tri-                                                                        methylene-1-hydroxymethyl-2-nor-13-trans-                                      prostene,1-ethylene ketal                       963  773   312        76       erythro-1,9-dioxo-11α,15α,16-tr                                    ihydroxy-                                                                      1-hydroxymethyl-2-nor-13-trans-prostene,                                       1-ethylene ketal                                964  773   312        69       threo-1,9-dioxo-11α,15α,16-trih                                    ydroxy-1-                                                                      hydroxymethyl-2-nor-13-trans-prostene,-                                        1-ethylene ketal                                965  773   312        74       erythro-1,9-dioxo-11α,15α-dihyd                                    roxy-16-                                                                       methoxy-1-hydroxymethyl-2-nor-13-trans-                                        prostene,1-ethylene ketal                       966  773   312        107      1,9-dioxo-11α,16-dihydroxy-1-hydroxym                                    eth-                                                                           yl-2-nor-13-trans-prostene,1-ethylene                                          ketal                                           967  773   312        130      1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    1-                                                                             hydroxymethyl-2-nor-13-trans-prostene,-                                        1-ethylene ketal                                968  773   312        134      1,9-dioxo-11α,16-dihydroxy-16-methyl-                                    1-                                                                             hydroxymethyl-2-nor-13-trans-17-trans-                                         prostadiene,1-ethylene ketal                    969  774   312        186      1,9-dioxo-11α,15α-dihydroxy-2,1                                    7,18,19,-                                                                      20-pentanor-16-phenoxy-1-hydroxymethyl-                                        13-trans-prostene,1-ethylene ketal              970  774   312        180      1,9-dioxo-11α,15α-dihydroxy-2,1                                    7,18,19,-                                                                      20-pentanor-16-m-trifluoromethylphenoxy-                                       1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                     971  773   312        194      1,9-dioxo-11α,16-dihydroxy-16-vinyl-1                                    -hy-                                                                           droxymethyl-2-nor-13-trans-prostene,1-                                         ethylene ketal                                  972  774   312        198      1,9-dioxo-11α,16-dihydroxy-16-cyclopr                                    op-                                                                            yl-1-hydroxymethyl-2-nor-13-trans-                                             prostene,1-ethylene ketal                       973  774   312        186b     1,9-dioxo-11α,15α-dihydroxy-2,1                                    8,19,20-                                                                       tetranor-17-phenyl-1-hydroxymethyl-13-                                         trans-prostene,1-ethylene ketal                 974  773   312        186e     1,9-dioxo-11α,15α-dihydroxy-2,1                                    8,19,20-                                                                       tetranor-17-(m-trifluorophenyl)-1-hydr-                                        oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                           975  773   312        186d     1,9-dioxo-11α,15α-dihydroxy-2,1                                    8,19,20-                                                                       tetranor-17-(p-methoxyphenyl)-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene             __________________________________________________________________________                                    ketal                                      

EXAMPLES 976-998

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 43 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 43. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain containing C₁₃. . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their componenet enantiomers.

                                      TABLE 43                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tin of                                                                           1,9-dioxo-hydroxymethylprostene and              Example                                                                             Example                                                                              of Example Example its diastereomer                                 __________________________________________________________________________     976  773   309        246     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-tetramethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                   977  774   309        245     nat-(and ent)-1,9-dioxo-11α,16-dihydro                                   xy-                                                                            16,17-tetramethylene-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        978  773   309        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   1                                                                              hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        979  773   309        243     nat-15S,16R-(and ent-15R, 16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                   .                                                                              hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        980  773   309        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   v                                                                              hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        981  773   309        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-trimethylene-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                      982  774   309        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                   xy-                                                                            15,16-pentamethylene-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                   983  773   309        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-h                                   y-                                                                             droxymethyl-13-trans-prostene,1-ethylene                                       ketal                                            984  773   309        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-dimethylene-1-h                                   y-                                                                             droxymethyl-13-trans-prostene,1-ethylene                                       ketal                                            985  773   309        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                   i                                                                              hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        986  773   309        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-tetramethylene-                                   1-                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        987  774   309        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-prost-                                       ene,1-ethylene ketal                             988  774   309        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-17,18,19,20-                                        tetranor-1-hydroxymethyl-13-trans-prost-                                       ene,1-ethylene ketal                             989  773   309        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene,1-                                           ethylene ketal                                   990  773   309        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (4-fluorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene,1-                                           ethylene ketal                                   991  774   309        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene,1-                                           ethylene ketal                                   992  774   309        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-16                                   -                                                                              (3-chlorophenoxy)-17,18,19,20-tetranor-                                        1-hydroxymethyl-13-trans-prostene,1-                                           ethylene ketal                                   993  773   309        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-trans-prost-                                       ene,1-ethylene ketal                             994  773   309        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       11α,15-dihydroxy-15,17-trimethylene-19                                   ,-                                                                             20-dinor-1-hydroxymethyl-13-ytrans-prost-                                      ene,1-ethylene ketal                             995  774   309        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-20                                   -                                                                              methyl-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                             996  774   309        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-2-                                   p                                                                              methyl-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                             997  774   309        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-tri-                                       nor-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                   998  774   309        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       11α,16-dihydroxy-16,17-trimethylene-16                                   -                                                                              (3-trifluoromethylphenoxy)-18,19,20-tri-                                       nor-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                   __________________________________________________________________________

EXAMPLES 994-1082

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 44 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 44; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomer is also formed and is part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 44                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example   1,9-dioxo-1-hydroxymethylprostene              __________________________________________________________________________      999 773   314        49        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      w                                                                              16-trimethylene-20-nor-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                   1000 773   314        50        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      .                                                                              16-trimethylene-20-methyl-5-cis-13-trans-                                      N                                                                              prostadiene,1-ethylene ketal                   1001 773   314        51        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      O                                                                              16-trimethylene-20-ethyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                   1002 774   314        193       1,9-dioxo-16-hydroxy-16-cyclopropyl-20-                                        ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   1003 774   314        195       1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1-                                      Z                                                                              hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                           1004 774   314        192       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                      5                                                                              droxymethyl-5-cis-13-trans-prostadiene,1-                                      3                                                                              ethylene ketal                                 1005 773   314        13        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      .                                                                              16-trimethylene-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                           1006 774   314        210a      1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-                                       vinyl-5-cis-13-trans-prostadiene,1-eth-                                        ylene ketal                                    1007 773   314        74        dl-erythro-1,9-dioxo-15-hydroxy-16-meth-                                       oxy-1-hydroxymethyl-5-cis-13-trans-prost-                                      h                                                                              adiene,1-ethylene ketal                        1008 773   314        77        dl-erythro-1,9-dioxo-15-hydroxy-16-eth-                                        oxy-1-hydroxymethyl-5-cis-13-trans-prost-                                      o                                                                              adiene,1-ethylene ketal                        1009 773   314        83        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-nor-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                   1010 773   314        84        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-methyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                   1011 773   314        85        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-ethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                   1012 773   314        86        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-19-methyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                   1013 773   314        87        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-5-cis-13-trans-17-trans-                                         prostratriene,1-ethylene ketal                 1014 773   314        69        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                       droxymethyl-5-cis-13-trans-prostadiene,1-                                      a                                                                              ethylene ketal                                 1015 773   314        88        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         nor-1-hydroxymethyl-5-cis-13-trans-                                            prostadiene,1-ethylene ketal                   1016 773   314        76        dl-erythro-1,9-dioxo-11α,15,16-trihy                                     dro-                                                                           1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           1017 773   314        89        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                   1018 773   314        90        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         ethyl-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   1019 773   314        91        dl-threo-1,9-dioxo-15,16-dihydroxy-19-                                         methyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                   1020 773   314        92        dl-threo-1,9-dioxo-15,16-dihydroxy-1-                                          hydroxymethyl-5-cis-13-trans-17-trans-                                         prostatriene,1-ethylene ketal                  1021 773   314        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-5-                                        cis-13-trans-prostadiene,1-ethylene                                            ketal                                          1022 773   314        108       1,9-dioxo-16-hydroxy-1-hydroxymethyl-19,-                                      f                                                                              20-dinor-5-cis-13-trans-prostadiene,1-                                         ethylene ketal                                 1023 773   314        109       1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                      r                                                                              19,20-trinor-5-cis-13-trans-prostadiene,1-                                     o                                                                              ethylene ketal                                 1024 773   314        110       1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                       nor-5-cis-13-trans-prostadiene,1-ethyl-                                        ene ketal                                      1025 773   314        144       1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy-                                      s                                                                              methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     t                                                                              ene ketal                                      1026 773   314        112       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                      .                                                                              methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     Z                                                                              ene ketal                                      1027 773   314        113       1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     5                                                                              ene ketal                                      1028 773   314        139a      1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                       1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           1029 773   314        115       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                       trans-17-cis-5-cis-prostatriene,1-ethyl-                                       ene ketal                                      1030 773   314        135       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      N                                                                              methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     O                                                                              ene ketal                                      1031 773   314        136       1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                       1-hydroxymethyl-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           1032 773   314        137       1,9-dioxo-16-hydroxy-16,20-dimethyl-1-hy-                                      4                                                                              droxymethyl-13-trans-5-cis-prostadiene,1-                                      .                                                                              ethylene ketal                                 1033 773   314        138       1,9-dioxo-16-hydroxy-17,17-dimethyl-1-hy-                                      c                                                                              droxymethyl-5-cis-13-trans-prostadiene                                         1-                                                                             ethylene ketal                                 1034 773   314        139       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      u                                                                              methyl-13-trans-17-trans-5-cis-prostatri-                                      b                                                                              ene,1-ethylene ketal                           1035 773   314        149       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                      e                                                                              methyl-13-trans-17-trans-5-cis-prostatri-                                      r                                                                              ene,1-ethylene ketal                           1036 773   314        150       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      o                                                                              methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     o                                                                              ene ketal                                      1037 773   314        151       1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                      t                                                                              droxymethyl-5-cis-13-trans-prostadiene,1-                                      .                                                                              ethylene ketal                                 1038 773   314        152       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                       trans-17-trans-5-cis-prostatriene,1-eth-                                       ylene ketal                                    1039 773   314        153       1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene,1-ethylene                                          ketal                                          1040 773   314        154       1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene,1-ethylene                                          ketal                                          1041 773   314        148a      1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                       methyl-5-cis-13-trans-17-trans-prostatri-                                      Z                                                                              ene,1-ethylene ketal                           1042 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymethy                                     l-5-                                                                 ylmethoxy-1-trans-                                                                       cis-13-trans-prostadiene,1-ethylene                                  octene (U.S. Pat.                                                                        ketal                                                                No. 3,873,607).                                          1043 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-methyl-1-hy                                     dr-                                                                  ylmethoxy-1-trans-                                                                       oxymethyl-5-cis-13-trans-prostadiene,1-                              nonene (U.S. Pat.                                                                        ethylene ketal                                                       No. 3,873,607).                                          1044 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-ethyl-1-hyd                                     roxy-                                                                ylmethoxy-1-trans-                                                                       methyl-5-cis-13-trans-prostadiene,1-eth-                             decene (U.S. Pat.                                                                        ylene ketal                                                          No. 3,873,607).                                          1045 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethyl                                     -1-                                                                  ylmethoxy-4,4-di-                                                                        hydroxymethyl-5-cis-13-trans-prostadi-                               methyl-1-trans-                                                                          ene,1-ethylene ketal                                                 octene (U.S. Pat.                                                              No. 3,873,607).                                          1046 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,17-dimethyl                                     -1-                                                                  ylmethoxy-5,5-di-                                                                        hydroxymethyl-5-cis-13-trans-prostadi-                               methyl-1-trans-                                                                          ene,1-ethylene ketal                                                 octene (U.S. Pat.                                                              No. 3,873,607).                                          1047 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-methyl-1-hy                                     dr-                                                                  ylmethoxy-4-meth-                                                                        oxymethyl-5-cis-13-trans-prostadiene,1-                              yl-1-trans-octene                                                                        ethylene ketal                                                       (U.S. Pat. No.                                                                 3,876,690).                                              1048 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-ethyl-1-hyd                                     roxy-                                                                ylmethoxy-4-ethyl-                                                                       methyl-5-cis-13-trans-prostadiene,1-eth-                             1-trans-octene                                                                           ylene ketal                                                          (U.S. Pat. No.                                                                 3,876,690).                                              1049 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,20-tetranor                                     -16-                                                                 ylmethoxy-4-cyclo-                                                                       cyclopetnyl-1-hydroxymethyl-5-cis-13-                                pentyl-1-trans-                                                                          trans-prostadiene,1-ethylene ketal                                   butene (U.S. Pat.                                                              No. 3,884,969).                                          1050 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,20-pentanor                                     -15-                                                                 ylmethoxy-3-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-5-cis-13-                                 hexyl-1-trans-                                                                           trans-prostadiene,1-ethylene ketal                                   pentene (U.S. Pat.                                                             No. 3,884,969).                                          1051 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-18,20-trinor-1                                     7-                                                                   ylmethoxy-5-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-5-cis-13-                                 hexyl-1-trans-                                                                           trans-prostadiene,1-ethylene ketal                                   pentene (U.S. Pat.                                                             No. 3,884,969).                                          1052 773   314        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-19,20-dinor-18                                     -                                                                    ylmethoxy-6-cyclo-                                                                       cyclopentyl-1-hydroxymethyl-5-cis-13-                                pentyl-1-trans-                                                                          trans-prostadiene,1-ethylene ketal                                   hexene (U.S. Pat.                                                              No. 3,884,969).                                          1053 773   314        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                     dr-                                                                  trimethylsilyl-                                                                          oxymethyl-5-cis-13-trans-prostadiene,1-                              oxy-trans-1-octene                                                                       ethylene ketal                                                       (Example 125)                                            1054 773   314        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-20-e                                     thyl-                                                                trimethylsilyl-                                                                          1-hydroxymethyl-5-cis-13-trans-prostadi-                             oxy-trans-1-decene                                                                       ene,1-ethylene ketal                                                 (Example 190a)                                           1055 774   314        159       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-fluorophenoxy-1-hydroxymethyl-5-                                      b                                                                              cis-13-trans-prostadiene,1-ethylene                                            ketal                                          1056 774   314        186       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-phenoxy-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene,1-ethylene ketal             1057 774   314        181       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-bromophenoxy-1-hydroxymethyl-5-                                       cis-13-trans-prostadiene,1-ethylene                                            ketal                                          1058 774   314        182       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-t-butylphenoxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene,1-ethylene                                          ketal                                          1059 774   314        183       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene,1-ethylene                                          ketal                                          1060 774   314        184       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-chlorophenoxy-1-hydroxymethyl-5-                                      .                                                                              cis-13-trans-prostadiene,1-ethylene                                            ketal                                          1061 774   314        180       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-m-trifluorophenoxy-1-hydroxymethyl-5-                                      u                                                                              cis-13-trans-prostadiene,1-ethylene                                            ketal                                          1062 774   314        185       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene,1-ethyl-                                     d                                                                              ene ketal                                      1063 774   314        186b      1,9-dioxo-15α-hydroxy-18,19,20-trino                                     r-                                                                             17-phenyl-1-hydroxymethyl-5-cis-13-trans-                                      a                                                                              prostadiene,1-ethylene ketal                   1064 774   314        186e      1,9-dioxo-15α-hydroxy-18,19,20-trino                                     r-17-                                                                          (m-trifluoromethylphenyl)-1-hydroxymeth-                                       yl-5-cis-13-trans-prostadiene,1-ethylene                                       ketal                                          1065 774   314        186d      1,9-dioxo-15α-hydroxy-18,19,20-trino                                     r-17-                                                                          (p-methoxyphenyl)-1-hydroxymethyl-5-cis-                                       13-trans-prostadiene,1-ethylene ketal          1066 773   315        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymethy                                     l-2-                                                                 ylmethoxy-1-trans-                                                                       nor-5-cis-13-trans-prostadiene,1-ethyl-                              octene (U.S. Pat.                                                                        ene ketal                                                            No. 3,873,607).                                          1067 773   315        185       1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                     droxy-                                                                         methyl-2-nor-5-cis-13-trans-prostadiene,-                                      .                                                                              1-ethylene ketal                               1068 773   315        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethyl                                     -1-hy-                                                               ylmethoxy-5,5-di-                                                                        droxymethyl-2-nor-5-cis-13-trans-prostadi-                                     5                                                                    methyl-octene                                                                            ene,1-ethylene ketal                                                 (U.S. Pat. No.                                                                 3,873,607).                                              1069 773   315        13        1,9-dioxo-15α-hydroxy-16,16-trimethy                                     lene-                                                                          1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   1070 773   315        76        erythro-1,9-dioxo-15α,16-dihydroxy-1                                     -hy-                                                                           droxymethyl-2-nor-5-cis-13-trans-prosta-                                       diene,1-ethylene ketal                         1071 773   315        69        threo-1,9-dioxo-15α,16-dihydroxy-1-h                                     ydr-                                                                           oxymethyl-2-nor-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           1072 773   315        74        erythro-1,9-dioxo-15α-hydroxy-16-met                                     hoxy-                                                                          1-hydroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                   1073 773   315        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                        nor-5-cis-13-trans-prostadiene,1-ethyl-                                        ene ketal                                      1074 773   315        130       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      N                                                                              methyl-2-nor-5-cis-13-trans-prostadiene-                                       1-ethylene ketal                               1075 773   315        134       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      O                                                                              methyl-2-nor-5-cis-13-trans-17-trans-                                          prostatriene,1-ethylene ketal                  1076 774   315        186       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                     pent-                                                                          anor-16-phenoxy-5-cis-13-trans-prostadi-                                       ene,1-ethylene ketal                           1077 774   315        180       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                     pent-                                                                          anor-16-m-trifluoromethylphenoxy-1-hydr-                                       oxy-5-cis-13-trans-prostadiene,1-ethylene                                      i                                                                              ketal                                          1078 774   315        194       1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                       methyl-2-nor-5-cis-13-trans-prostadiene,-                                      e                                                                              1-ethylene ketal                               1079 774   315        198       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                      n                                                                              droxymethyl-2-nor-5-cis-13-trans-prosta-                                       diene,1-ethylene ketal                         1080 774   315        186b      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                     ra-                                                                            nor-17-phenyl-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene,1-ethylene ketal             1081 773   315        186e      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                     ra-                                                                            nor-17-(m-trifluorophenyl)-1-hydroxymeth-                                      Z                                                                              yl-5-cis-13-trans-prostadiene,1-ethylene                                       ketal                                          1082 773   315        186d      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                     ra-                                                                            nor-17-(p-methoxyphenyl)-1-hydroxymeth-                                        yl-5-cis-13-trans-prostadiene,1-ethylene                                       ketal                                          __________________________________________________________________________

EXAMPLES 1083-1105

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 45 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 45. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃ . . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      TABLE 45                                     __________________________________________________________________________                           Vinyl Iodide or                                          Example                                                                             Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tin of                                                                           1,9-dioxo-1-hydroxymetylprostene and             Example                                                                             Example                                                                              of Example Example its diastereomer                                 __________________________________________________________________________     1083 773   314        246     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      tetramethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-5-cis-13-trans-prostadi-                                         ene,1-ethylene ketal                             1084 774   314        245     nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                      tetramethylene-18,19,20-trinor-1-hydr-                                         oxymethyl-5-cis-13-trans-prostadiene,1-                                        ethylene ketal                                   1085 773   314        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene,1-eth-                                       ylene ketal                                      1086 773   314        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene,1-eth-                                       ylene ketal                                      1087 773   314        251     nat-15S,16S-(and ent-15R,16R9-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene,1-eth-                                       ylene ketal                                      1088 773   314        247     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      trimethylene-17,18,19,20-tetranor-1-hy-                                        droxymethyl-13-trans-5-cis-prostadiene                                         1-ethylene ketal                                 1089 774   314        248     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      pentamethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             1090 773   314        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-5-cis-prostadiene,1-eth-                                       ylene ketal                                      1091 773   314        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-5-cis-prostadiene,1-eth-                                       ylene ketal                                      1092 773   314        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hydr-                                        oxymethyl-13-trans-5-cis-prostadiene,1-                                        ethylene ketal                                   1093 773   314        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hydr-                                        oxymethyl-13-trans-5-cis-prostadiene,1-                                        ethylene ketal                                   1094 774   314        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene,1-ethylene ketal                          1095 774   314        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-17,18,19,20-tetra-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene,1-ethylene ketal                          1096 774   314        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(4-flu-                                       orophenoxy)-17,18,19,20-tetranor-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene,1-                                        ethylene ketal                                   1097 774   314        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(4-flu-                                       orophenoxy)-17,18,19,20-tetranor-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene,1-                                        ethylene ketal                                   1098 774   314        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             1099 774   314        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             1100 773   314        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene,1-ethylene ketal                          1101 773   314        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-5-cis-prost-                                      adiene, 1-ethylene ketal                         1102 774   314        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-20-methyl-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                             1103 774   314        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-20-methyl-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                             1104 774   314        264     nat-16R,17S,-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             1105 774   314        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-5-cis-prostadi-                                         ene,1-ethylene ketal                             __________________________________________________________________________

EXAMPLES 1106-1189

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 46 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions, only the C₁₅ or C₁₆ -normal isomers are listed in Table 46; it should be understood that the corresponding C₁₅ or C₁₆ -epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 46                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of        Vinyl Tin of                                             Example                                                                             Example                                                                              Cyclopent-2-en-1-one                                                                      Example   1,9-dioxo-1-hydroxymethylprostene              __________________________________________________________________________     1106 773   283        49        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      N                                                                              16-trimethylene-20-nor-13-trans-prostadi-                                      O                                                                              ene,1-ethylene ketal                           1107 773   283        50        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      0                                                                              16-trimethylene-20-methyl-13-trans-prost-                                      .                                                                              adiene,1-ethylene ketal                        1108 773   283        51        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      a                                                                              16-trimethylene-20-ethyl-13-trans-prosta-                                      l                                                                              diene,1-ethylene ketal                         1109 774   283        193       1,9-dioxo-16-hydroxy-16-cyclopropyl-20-                                        ethyl-1-hydroxymethyl-13-trans-prostene,-                                      p                                                                              1-ethylene ketal                               1110 774   283        195       1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1-                                      h                                                                              hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                      1111 774   283        192       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                      a                                                                              droxymethyl-13-trans-prostene,1-ethylene                                       ketal                                          1112 773   283        13        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                      .                                                                              16-trimethylene-13-trans-prostene,1-ethyl-                                     Z                                                                              ene ketal                                      1113 774   283        210a      1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-                                       vinyl-13-trans-prostene,1-ethylene ketal       1114 773   283        74        dl-erythro-1,9-dioxo-15-hydroxy-16-meth-                                       oxyl-1-hydroxymethyl-13-trans-prostene,1-                                      6                                                                              ethylene ketal                                 1115 773   283        777       dl-erythro-1,9-dioxo-15-hydroxy-16-ethoxy-                                     1                                                                              1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                    1116 773   283        83        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-nor-13-trans-prostene,-                                       1-ethylene ketal                               1117 773   283        84        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-methyl-13-trans-prost-                                        ene,1-ethylene ketal                           1118 773   283        85        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-20-ethyl-13-trans-prost-                                         ene,1-ethylene ketal                           1119 773   283        86        dl-erythro-1,9-dioxo-15,16-dihydroxy-19-                                       methyl-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                           1120 773   283        87        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-13-trans-17-trans-prosta-                                        diene,1-ethylene ketal                         1121 773   283        69        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                       droxymethyl-13-trans-prostene,1-ethylene                                       ketal                                          1122 773   283        88        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         nor-1-hydroxymethyl-13-trans-prostene,-                                        1-ethylene ketal                               1123 773   283        76        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                      1124 773   283        89        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         methyl-1-hydroxymethyl-13-trans-prosta-                                        ene,1-ethylene ketal                           1125 773   283        90        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                         ethyl-1-hydroxymethyl-13-trans-prost-                                          ene,1-ethylene ketal                           1126 773   283        91        dl-threo-1,9-dixo-15,16-dihydroxy-19-                                          methyl-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                           1127 773   283        92        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                       droxymethyl-13-trans-17-trans-prostadi-                                        ene,1-ethylene ketal                           1128 773   283        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                       trans-prostene,1-ethylene ketal                1129 773   283        108       1,9-dioxo-16-hydroxy-1-hydroxymethyl-19-                                       20-dinor-13-trans-prostene,1-ethylene                                          ketal                                          1130 773   283        109       1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                      N                                                                              19,20-trinor-13-trans-prostene,1-ethylene                                      O                                                                              ketal                                          1131 773   283        110       1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                       nor-13-trans-prostene,1-ethylene ketal         1132 773   283        144       1,9-dioxo-16-hydroxy-17-meythyl-1-hydroxy-                                     .                                                                              methyl-13-trans-prostene,1-ethylene                                            ketal                                          1133 773   283        112       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                      s                                                                              methyl-13-ytrans-prostene,1-ethylene                                           ketal                                          1134 773   283        113       1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene                                            ketal                                          1135 773   283        139a      1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                       1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                    1136 773   283        115       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                       trans-17-cis-prostadiene,1-ethylene                                            ketal                                          1137 773   283        135       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      y                                                                              methyl-13-trans-prostene,1-ethylene                                            ketal                                          1138 773   283        136       1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                       1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                    1139 773   283        137       1,9-dioxo-16-hydroxy-16,20-dimethyl-1-hy-                                      m                                                                              droxymethyl-13-trans-prostene,1-ethylene                                       ketal                                          1140 773   283        138       1,9-dioxo-16-hydroxy-17,17-dimethyl-1-                                         hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                      1141 773   283        139       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      .                                                                              methyl-13-trans-17-trans-prostadiene,1-                                        ethylene ketal                                 1142 773   283        149       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                      Z                                                                              methyl-13-trans-17-trans-prostadiene,1-                                        ethylene ketal                                 1143 773   283        150       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      6                                                                              methyl-13-trans-prostene,1-ethylene                                            ketal                                          1144 773   283        151       1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                      2                                                                              droxymethyl-13-trans-prostene,1-etylene                                        ketal                                          1145 773   283        152       1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                      .                                                                              trans-17-trans-prostadiene,1-ethylene                                          ketal                                          1146 773   283        153       1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal             1147 773   283        154       1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal             1148 773   283        148a      1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                       methyl-13-trans-17-trans-prostadiene,1-                                        ethylene ketal                                 1149 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymethy                                     l-                                                                   ylmethoxy-1-trans-                                                                       13-trans-prostadiene,1-ethylene ketal                                octene (U.S. Pat.                                                              No. 3,873,607).                                          1150 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-methyl-1-hy                                     dr-                                                                  ylmethoxy-1-trans-                                                                       oxymethyl-13-trans-prostene,1-ethylene                               nonene (U.S. Pat.                                                                        ketal                                                                No. 3,873,607).                                          1151 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-ethyl-1-hyd                                     r-                                                                   ylmethoxy-1-trans-                                                                       oxymethyl-13-trans-prostene,1-ethylene                               decene (U.S. Pat.                                                                        ketal                                                                No. 3,873,607).                                          1152 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethyl                                     -1-                                                                  ylmethoxy-4,4-di-                                                                        hydroxymethyl-13-trans-prostene,1-eth-                               methyl-1-trans-                                                                          ylene ketal                                                          octene (U.S. Pat.                                                              No. 3,873,607).                                          1153 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,17-dimethyl                                     -1-                                                                  ylmethoxy-5,5-di-                                                                        hydroxymethyl-13-trans-prostene,1-eth-                               methyl-1-trans-                                                                          ylene ketal                                                          octene (U.S. Pat.                                                              No. 3,873,607).                                          1154 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-methyl-1-hy                                     dr-                                                                  ylmethoxy-4-meth-                                                                        oxymethyl-13-trans-prostene,1-ethylene                               yl-1-trans-octene                                                                        ketal                                                                (U.S. Pat. No.                                                                 3,876,690).                                              1155 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-ethyl-1-hyd                                     r-                                                                   ylmethoxy-4-ethyl-                                                                       oxymethyl-13-trans-prostene,1-ethylene                               1-trans-octene                                                                           ketal                                                                (U.S. Pat. No.                                                                 3,876,690).                                              1156 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,20-tetranor                                     -                                                                    ylmethoxy-4-cyclo-                                                                       16-cyclopentyl-1-hydroxymethyl-13-trans-                             pentyl-1-trans-                                                                          prostene,1-ethylene ketal                                            butene (U.S. Pat.                                                              No. 3,884,969).                                          1157 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,20-pentanor                                     -15-                                                                 ylmethoxy-3-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-13-trans-                                 hexyl-1-trans-                                                                           prostene,1-ethylene ketal                                            pentene (U.S. Pat.                                                             No. 3,884,969).                                          1158 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-18,20-trinor-1                                     7-                                                                   ylmethoxy-5-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-13-trans-                                 hexyl-1-trans-                                                                           prostene,1-ethylene ketal                                            pentene (U.S. Pat.                                                             No. 3,884,969).                                          1159 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-19,20-dinor-18                                     -                                                                    ylmethoxy-6-cyclo-                                                                       cyclopentyl-1-hydroxymethyl-13-trans-                                pentyl-1-trans-                                                                          prostene,1-ethylene ketal                                            hexene (U.S. Pat.                                                              No. 3,884,969).                                          1160 773   283        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                     dr-                                                                  trimethylsilyl-                                                                          oxymethyl-13-trans-prostene,1-ethylene                               oxy-trans-1-octene                                                                       ketal                                                                (Example 125).                                           1161 773   283        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-20-e                                     th-                                                                  trimethylsilyl-                                                                          yl-1-hydroxymethyl-13-trans-prostene,1-                              oxy-trans-1-decene                                                                       ethylene ketal                                                       (Example 190a).                                          1162 774   283        159       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-fluorophenoxy-1-hydroxymethyl-                                        13-trans-prostene,1-ethylene ketal             1163 774   283        186       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-phenoxy-1-hydroxymethyl-13-trans-                                       prostene,1-ethylene ketal                      1164 774   283        181       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-bromophenoxy-1-hydroxymethyl-13-                                      a                                                                              trans-prostene,1-ethylene ketal                1165 774   283        182       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-t-butylphenoxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal             1166 774   283        183       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal             1167 774   283        184       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-p-chlorophenoxy-1-hydroxymethyl-                                        13-trans-prostene,1-ethylene ketal             1168 774   283        180       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-m-trifluorophenoxy-1-hydroxymethyl-                                        13-trans-prostene,1-ethylene ketal             1169 774   283        185       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                     tra-                                                                           nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene                                            ketal                                          1170 774   283        186b      1,9-dioxo-15α-hydroxy-18,19,20-trino                                     r-7-                                                                           phenyl-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                           1171 774   283        186e      1,9-dioxo-15α-hydroxy-18,19,20-trino                                     r-17-                                                                          (m-trifluoromethylphenyl)-1-hydroxymeth-                                       yl-13-trans-prostene,1-ethylene ketal          1172 774   283        186d      1,9-dioxo-15α-hydroxy-18,19,20-trino                                     r-17-                                                                          (p-methoxyphenyl)-1-hydroxymethyl-13-                                          trans-prostene,1-ethylene ketal                1173 773   310        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymethy                                     l-2-                                                                 ylmethoxy-1-trans-                                                                       nor-13-trans-prostene,1-ethylene ketal                               octene (U.S. Pat.                                                              No. 3,873,607).                                          1174 773   310        185       1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                     dr-                                                                            oxymethyl-2-nor-13-trans-prostene,1-eth-                                       ylene ketal                                    1175 773   310        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethyl                                     -1-                                                                  ylmethoxy-5,5-di-                                                                        hydroxymethyl-2-nor-13-trans-prostene,-                              methyl-octene                                                                            1-ethylene ketal                                                     (U.S. Pat. No.                                                                 3,873,607).                                              1176 773   310        13        1,9-dioxo-15α-hydroxy-16,16-trimethy                                     lene-                                                                          1-hydroxymethyl-2-nor-13-trans-prostene,                                       1-ethylene ketal                               1177 773   310        76        erythro-1,9-dioxo-15α,16-dihydroxy-1                                     -hy-                                                                           droxymethyl-2-nor-13-trans-prostene,1-                                         ethylene ketal                                 1178 773   310        69        threo-1,9-dioxo-15α,16-dihydroxy-1-h                                     ydr-                                                                           oxymethyl-2-nor-13-trans-prostene,1-eth-                                       ylene ketal                                    1179 773   310        74        erythro-1,9-dioxo-15α-hydroxy-16-met                                     hoxy-                                                                          1-hydroxymethyl-2-nor-13-trans-prostene                                        1-ethylene ketal                               1180 773   310        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                        nor-13-trans-prostene,1-ethylene ketal         1181 773   285        130       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      O                                                                              methyl-2-nor-13-trans-prostene,1-ethylene                                      5                                                                              ketal                                          1182 773   285        134       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                      .                                                                              methyl-2-nor-13-trans-17-trans-prostadi-                                       ene,1-ethylene ketal                           1183 774   285        186       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                     g                                                                              pentanor-16-phenoxy-1-hydroxymethyl-13-                                        trans-prostene,1-ethylene ketal                1184 774   285        180       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                     a                                                                              pentanor-16-m-trifluoromethylphenoxy-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                      1185 773   285        194       1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                       methyl-2-nor-13-trans-prostene,1-ethylene                                      m                                                                              ketal                                          1186 774   285        198       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-                                         hydroxymethyl-2-nor-13-trans-prostene,-                                        1-ethylene ketal                               1187 774   285        186b      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                     ranor-                                                                         17-phenyl-1-hydroxymethyl-13-trans-pro-                                        stene,1-ethylene ketal                         1188 773   285        186e      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                     ranor-                                                                         17-(m-trifluorophenyl)-1-hydroxymethyl-                                        13-trans-prostene,1-ethylene ketal             1189 773   285        186d      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                     ranor-                                                                         17-(p-methoxyphenyl)-1-hydroxymethyl-13-                                       trans-prostene,1-ethylene                      __________________________________________________________________________                                     ketal                                     

EXAMPLES 1190-1212

By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 47 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 47. It should be understood that the other diastereoisomer is also found which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetri carbon atoms on the β-chain (the chain containing C₁₃ . . . C₁₄ etc.) to that of the respective nat and end forms of the listed diastereoisimer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      TABLE 47                                     __________________________________________________________________________                           Vinyl Iodide or                                               Method of                                                                            Cyclopent-2-en-1-one                                                                      Vinyl Tin of                                                                           1,9-dioxo-1-hydroxymethylprostene and            Example                                                                             Example                                                                              of Example Example its diastereomer                                 __________________________________________________________________________     1190 773   283        246     nat-(and ent)-1,9-dioxo-16-hydroxy-15,16-                                      tetramethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        1191 774   283        245     nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                      tetrametylene-18,19,20-trinor-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene ketal        1192 773   283        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydro-                                         methyl-13-trans-prostene,1-ethylene ketal        1193 773   283        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene ketal        1194 773   283        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene ketal        1195 773   283        247     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      trimethylene-17,18,19,20-tetranor-1-hydr-                                      oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                            1196 773   283        248     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                      pentamethylene-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        1197 773   283        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene ketal        1198 773   283        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       15-hydroxy-15,17-dimethylene-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene ketal        1199 773   283        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hydr-                                        oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                            1200 773   283        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hydr-                                        oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                            1201 774   283        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-17,18,19,20-tetranor-                                     1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                      1202 774   283        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-17,18,19,20-tetranor-                                     1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                      1203 773   283        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(4-flu-                                       orophenoxy)-17,18,19,20-tetranor-1-hydr-                                       oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                            1204 773   283        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(4-flu-                                       orophenoxy)-17,18,19,20-tetranor-1-hydr-                                       oxymethyl-13-trans-prostene,1-ethylene                                         ketal                                            1205 774   283        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        1206 774   283        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-16-(3-                                           chlorophenoxy)-17,18,19,20-tetranor-1-                                         hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        1207 773   283        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                       15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                   1208 773   283        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                       15-hydroxy-15,17-trimethylene-19,20-di-                                        nor-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                   1209 774   283        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-20-methyl-                                       1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                      1210 774   283        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-20-methyl-                                       1-hydroxymethyl-13-trans-prostene,1-eth-                                       ylene ketal                                      1211 774   283        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        1212 774   283        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                       16-hydroxy-16,17-trimethylene-16-(3-tri-                                       fluoromethylphenoxy)-18,19,20-trinor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                       ene ketal                                        __________________________________________________________________________

EXAMPLE 1213 1,9-Dioxo-11α,16-dihydroxy-16-vinyl-1-acetoxymethyl-5-cis-13-trans prostadiene

To a solution of 0.1 g of 1,9-dioxo-11α,16-dihydroxy-16-vinyl-1-hydroxymethyl-5-cis-13-trans prostadiene in 0.75 ml of pyridine is added 0.026 g of acetic anhydride. After standing overnight, the pyridine is removed at reduced pressure. The residue is chromatographed on a dry column of silica gel eluting with benzene-ethylacetate 1:1 to give 0.049 g of the product.

In accordance with the above example 1213 the 1-hydroxymethyl analogs of Examples 319-769 are treated with acetic anhydride, propionic anhydride, n-butyric anhydride and n-valeric anhydride to give the respective 1-acetoxymethyl, 1-propoxymethyl, 1-n-butoxymethyl and 1-n-peutoxymethyl analogs. 

I claim:
 1. An optically active compound of the formula: ##STR115## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR116## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR117## wherein R₄ is selected from the group consisting of hydrogen and methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₇ is selected from the group consisting of C₂ -C₄, R₈ is selected from the group consisting of C₁ -C₂ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl, p is an integer from 0 to 3, and q is 1 or 2; the racemic mixture thereof.
 2. An optically active compound according to claim 1, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR118##
 3. An optically active compound according to claim 1, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR119## wherein R is an previously defined.
 4. An optically active compound according to claim 2 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR120## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previously defined.
 5. An optically active compound according to claim 2, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR121## wherein R₇, p and q are as previously defined.
 6. An optically active compound according to claim 5, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR122## wherein p and q are as previously defined.
 7. The optically active compound according to claim 4, 1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-5-cis-13-trans-prostadeine and the racemic mixture thereof.
 8. The optically active compound according to claim 4, 1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof
 9. The optically active compound according to claim 4, 1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16,16-dimethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 10. The optically active compound according to claim 4, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 11. The optically active compound according to claim 4, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16,16-trimethylene-5-cis-13-trans-postadiene and the racemic mixture thereof.
 12. The optically active compound according to claim 4, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16,16-trimethylene-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 13. The optically active compound according to claim 4, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-15-methyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 14. The optically active compound according to claim 4, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-15-methyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 15. The optically active compound according to claim 4, 1,9-dioxo-15α-hydroxy-1-hydroxymethyl-15-methyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 16. The racemic optically active compound according to claim 4, -1,9-dioxo-15α-hydroxy-1-hydroxymethyl-16,16-trimethylene-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 17. The optically active compound according to claim 4, -1,9-dioxo-15α-hydroxy-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 18. The optically active compound according to claim 5, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl, 17,17-dimethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 19. An optically active compound according to claim 3 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR123## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previously defined.
 20. An optically active compound according to claim 3, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR124## wherein R₇, p and q are as previously defined.
 21. An optically active compound according to claim 20 wherein R₁, R₃, C₁₃₋₁₄ and f are as previously defined; and R is a moiety selected from the group consisting of ##STR125## wherein p and q are as previously defined.
 22. The optically active compound according to claim 19, -1,9-dioxo-11α,15α-dihydroxy-1-acetoxymethyl-5-cis-13-trans-prastadiene and the racemic mixture thereof.
 23. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-acetoxymethyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 24. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-propanoyloxymethyl-16,16-trimethylene-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 25. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-acetoxymethyl-15-methyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 26. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-n-butanoyloxymethyl-15-methyl-20-ethyl-5-cis- 13-cis-and the racemic mixture thereof.
 27. The optically active compound according to claim 19, -1,9-dioxo-15α-hydroxy-1-acetoxymethyl-15-methyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 28. The optically active compound according to claim 19, -1,9-dioxo-15α-hydroxy-1-acetoxymethyl-16,16-trimethylene-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 29. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-acetoxymethyl-16,16-dimethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 30. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-acetoxymethyl-16-methyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 31. The optically active compound according to claim 19, -1,9-dioxo-11α, 15α-dihydroxy-1-acetoxymethyl-16,16-trimethylene-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 32. The optically active compound according to claim 19, -1,9-dioxo-15α-hydroxy-1-acetoxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 33. The optically active compound according to claim 20, -1,9-dioxo-11α, 15α-dihydroxy-1-n-pentanoyloxymethyl-17,17-dimethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 34. An optically active compound of the formula: ##STR126## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR127## wherein R is selected from the group consisting of C₁ -C₄. ##STR128## wherein R₄ is selected from the group consisting of hydrogen and methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₇ is selected from the group consisting of C₂ -C₄, R₈ is selected from the group consisting of C₁ -C₂ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl, p is an intege from 0 to 3, and q is 1 or 2; the racemic mixture thereof
 35. An optically active compound according to claim 34 wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR129##
 36. An optically active compound according to claim 34 wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR130## wherein R is as previously defined.
 37. An optically active compound according to claim 35 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected fromthe group consisting of ##STR131## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previously defined.
 38. An optically active compound according to claim 35 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR132## wherein R₇, p and q are as previously defined.
 39. An optically active compound according to claim 38 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR133## wherein p and q are as previously defined.
 40. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 41. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 42. The optically active compound according to claim 37, 1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16,16-dimethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 43. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 44. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxyl-1-hydroxymethyl-16,16-trimethyl-ene-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 45. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-16,16-trimethylene-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 46. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-15-methyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 47. The optically active compound according to claim 37, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-15-methyl-20-ethyl-5-cis-13-trans prostadiene-1-ethylene ketal and the racemic mixture thereof.
 48. The optically active compound according to claim 37, -1,9-dioxo-15α-hydroxy-1-hydroxymethyl-15-methyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 49. The optically active compound according to claim 37, -1,9-dioxo-15α-hydroxy-1-hydroxymethyl-16,16-trimethylene-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 50. The optically active compound according to claim 37, 1,9-dioxo-15α-bydroxy-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 51. The optically active compound according to claim 38, -1,9-dioxo-11α, 15α-dihydroxy-1-hydroxymethyl-17,17-dimethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 52. An optically active compound of the formula: ##STR134## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R' is a radical selected from the group consisting of ##STR135## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR136## wherein R₆ is selected from the group consisting of C₃ -C₆ alkyl, R₇ is selected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consisting of C₁ -C₄ alkyl; the racemic mixture thereof.
 53. An optically active compound according to claim 52, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR137##
 54. An optically active compound according to claim 52 wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR138## wherein R is as previously defined.
 55. An optically active compound according to claim 53, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined, and R₂ is a moiety selected from the group consisting of ##STR139## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previously defined.
 56. An optically active compound according to claim 53 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR140## wherein R₇ is as previously defined.
 57. An optically active compound according to claim 56, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR141## wherein R₇ is as previously defined.
 58. An optically active compound according to claim 55, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR142## wherein R₆, R₁₁ and R₁₂ are as previously defined.
 59. An optically active compound according to claim 55, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR143## wherein R₁₀ and R₁₁ are as previously defined.
 60. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 61. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-vinyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 62. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-cyclopropyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 63. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 64. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 65. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16,20-diethyl-5-cis-13-trans-prostadiene, and the racemic mixturre thereof.
 66. The optically active compound according to claim 55, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 67. The optically active compound according to claim 57, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-17-methyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 68. The optically active compound according to claim 57, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-17,20-dimethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 69. The optically active compound according to claim 57, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-17-methyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 70. The optically active compound according to claim 58, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 71. The optically active compound according to claim 58, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 72. The optically active compound according to claim 58, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 73. The optically active compound according to claim 58, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-20-ethyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 74. The optically active compound according to claim 59, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 75. The optically active compound according to claim 59, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 76. The optically active compound according to claim 59, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 77. The optically active compound according to claim 59, selected from the group consisting of 1,9-dioxo-11α. 16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 78. An optically active compound according to claim 54 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined, and R₂ is a moiety selected from the group consisting of ##STR144## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previously defined.
 79. An optically active compound according to claim 54, wherei R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR145## wherein R₇ is as previously defined.
 80. An optically active compound according to claim 79, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR146## wherein R₇ is as previously defined.
 81. An optically active compound according to claim 78, wherein R₁, R₃, C₁₂ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR147## wherein R₆, R₁₁ and R₁₂ are as previously defined.
 82. An optically active compound according to claim 78, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR148## wherein R₁₀ and R₁₁ are as previously defined.
 83. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-16-vinyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 84. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-16-vinyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 85. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-16-cyclopropyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 86. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 87. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy--acetoxymethyl-16-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 88. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-16,20-diethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 89. The optically active compound according to claim 78, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-16-vinyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 90. The optically active compound according to claim 80, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-17-methyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 91. The optically active compound according to claim 80, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-17,20-dimethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 92. The optically active compound according to claim 80, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-17-methyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 93. The optically active compound according to claim 81, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 94. The optically active compound according to claim 81, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 95. The optically active compound according to claim 81, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 96. The optically active compound according to claim 81, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-acetoxymethyl-20-ethyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 97. The optically active compound according to claim 82, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-acetoxymethyl-16-methyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 98. The optically active compound according to claim 82, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-acetoxymethyl-16-methyl-20-ethyl-5-cis-13-trans-prostadiene, and the racemic mixture thereof.
 99. The optically active compound according to claim 82, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-acetoxymethyl-16-methyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 100. The optically active compound according to claim 82, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-acetoxymethyl-16-methyl-20-ethyl-5-cis-17-trans-13-trans-prostatriene, and the racemic mixture thereof.
 101. An optically active compound of the formula: ##STR149## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR150## wherein R is selected from the group consisting of C₁ -C₄ alkyl, R₂ is a moiety selected from the group consisting of ##STR151## wherein R₆ is selected from the group consisting of C₃ -C₆ alkyl, R₇ is selected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consisting of C₁ -C₄ alkyl; the racemic mixture thereof.
 102. An optically active compound according to claim 101, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR152##
 103. An optically active compound according to claim 101, wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR153## wherein R is as previously defined.
 104. An optically active compound according to claim 102, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined, and R₂ is a moiety selected from the group consisting of ##STR154## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previously defined.
 105. An optically active compound according to claim 102, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR155## wherein R₇ is as previously defined.
 106. An optically active compound according to claim 105, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR156## wherein R₇ is as previously defined.
 107. An optically active compound according to claim 104, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR157## wherein R₆, R₁₁ and R₁₂ are as previously defined.
 108. An optically active compound according to claim 104, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR158## wherein R₁₀ and R₁₁ are as previously defined.
 109. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 110. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-vinyl-20-ethyl-5-cis-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 111. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-cyclopropyl-5-cis-13trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 112. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 113. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α,16αand 16β-dihydroxy-1-hydroxymethyl-16-cyclopropyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 114. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16,20-diethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 115. The optically active compound according to claim 104, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 116. The optically active compound according to claim 106, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-17-methyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 117. The optically active compound according to claim 106, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-17,20-dimethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 118. The optically active compound according to claim 106, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-17-methyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 119. The optically active compound to claim 107, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 120. The optically active compound according to claim 107, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 121. The optically active compound according to claim 107, selected from the group consisting of 1,9-dioxo-11α, 16α and 16β-dihydroxy-1-hydroxymethyl-5-cis-17-trans-13-trans-prostatriene-1-ethylene ketal, and the racemic mixture thereof.
 122. The optically active compound according to claim 107, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-20-ethyl-5-cis-17-trans-13trans-prostatriene-1-ethylene ketal, and the racemic mixture thereof.
 123. The optically active compound according to claim 108, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 124. The optically active compound according to claim 108, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal, and the racemic mixture thereof.
 125. The optically active compounds according to claim 108, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-16-trans-13-trans-prostatriene-1-ethylene ketal, and the racemic mixture thereof.
 126. The optically active compound according to claim 108, selected from the group consisting of 1,9-dioxo-11α,16α and 16β-dihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-5-cis-16-trans-13-trans-prostatriene-1-ethylene ketal, and the racemic mixture thereof.
 127. An optically active compound of the formula: ##STR159## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R is a radical selected from the group consisting of ##STR160## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR161## wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof.
 128. An optically active compound according to claim 1, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR162##
 129. An optically active compound according to claim 1, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR163## wherein R is as previously defined.
 130. An optically active compound according to claim 128, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR164## wherein R₁₁ is as previously defined.
 131. An optically active compound according to claim 128, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR165## wherein R₆ and R₈ are as previously defined.
 132. The optically active compound according to claim 130, erythro-11α, 15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 133. The optically active compound according to claim 130, erythro-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 134. The optically active compound according to claim 130, -threo-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 135. The optically active compound according to claim 130, -threo-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 136. The optically active compound according to claim 131, erythro-11α,15α-dihydroxy-1,9-dioxo-1-hydroxymethyl-16-methoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 137. An optically active compound according to claim 129 wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR166## wherein R₁₁ is as previously defined.
 138. An optically active compound according to claim 129, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR167## wherein R₆ and R₈ are as previously defined.
 139. The optically active compound according to claim 137, erythro-11α,15α,16-trihydroxy-1,9-dioxo-1-n-propanoyloxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 140. The optically active compound according to claim 137, erythro-11α,15α, 16-trihydroxy-1,9-dioxo-1-acetoxymethyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 141. The optically active compound according to claim 137, threo-11α,15α,16-trihydroxy-1,9-dioxo-1-acetoxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 142. The optically active compound according to claim 137, threo-11α, 15α,16-trihydroxy-1,9-dioxo-1-acetoxymethyl-20-ethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 143. The optically active compound according to claim 138, erythro-11α, 15α-dihydroxy-1,9-dioxo-1-acetoxymethyl-16-methoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 144. An optically active compound of the formula: ##STR168## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of ##STR169## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR170## wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof.
 145. An optically active compound according to claim 144, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR171##
 146. An optically active compound according to claim 144 wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR172## wherein R is as previously defined.
 147. An optically active compound according to claim 145, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR173## wherein R₁₁ is as previously defined.
 148. An optically active compound according to claim 145, wherein R₁, R₃, C₁₃ -C₁₄ and f are as previously defined; and R₂ is a moiety selected from the group consisting of ##STR174## wherein R₆ and R₈ are as previously defined.
 149. The optically active compound according to claim 147, erythro-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 150. The optically active compound according to claim 147, erythro-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 151. The optically active compound according to claim 147, threo-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 152. The optically active compound according to claim 147, threo-11α,15α,16-trihydroxy-1,9-dioxo-1-hydroxymethyl-20-ethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 153. The optically active compound according to claim 148, erythro-11α,15α-dihydroxy-1,9-dioxo-1-hydroxymethyl-16-methoxy-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 154. An optically active compound of the formula: ##STR175## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R' is a radical selected from the group consisting of ##STR176## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of ##STR177## wherein X is a divalent radical selected from the group consisting of ##STR178## wherein R₅ is selected from the group consisting of C₁ -C₇ alkyl, hydrogen and a phenoxy group optionally substituted from the group consisting of halogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is a trivalent radical selected from the group consisting of ##STR179## Z is a divalent radical selected from the group consisting of --O and --CH₂ --, m is zero or an integer from 1 to 4, inclusive, n is zero or an integer from 1 to 4, inclusive, with the proviso that the sum of m and n has the value of 1 to 4, s is zero or the integer 1, t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof.
 155. An optically active compound of the formula: ##STR180## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is selected from the group consisting of: ##STR181## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of: ##STR182## wherein t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof; and the mirror image thereof.
 156. An optically active compound according to claim 155, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR183##
 157. An optically active compound according to claim 155, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR184## wherein R is as previously defined.
 158. A compound according to claim 156 wherein f is
 3. 159. The optically active compound according to claim 158, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-trifluoromethylphenoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 160. The optically active compound according to claim 158, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-chlorophenoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 161. The optically active compound according to claim 158, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-17,20-tetranor-16-p-fluorophenoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 162. The optically active compound according to claim 156, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-18,20-trinor-17-phenyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 163. The optically active compound according to claim 156, nat-1,9-dioxo-11α,15-dihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 164. The optically active compound according to claim 156, nat-1,9-dioxo-11α,16-dihydroxy-16,17-tetramethylene-18,19,20-trinor-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 165. The optically active compound according to claim 156, nat-15S,16R-1,9-dioxo-11α,15-dihydroxy-15,16-trimethylene-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 166. The optically active compound according to claim 156, nat-15S,16S-1,9-dioxo-11α,15-dihydroxy-15,16-trimethylene-1-hydroxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 167. A compound according to claim 157 wherein f is
 3. 168. The optically active compound according to claim 167, 1,9-dioxo-11α,15-dihydroxy-1-acetoxymethyl-17,20-tetranor-16-m-trifluoromethylphenoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 169. The optically active compound according to claim 167, 1,9-dioxo-11α,15α-dihydroxy-1-acetoxymethyl-17,20-tetranor-16-m-chlorophenoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 170. The optically active compound according to claim 167, 1,9-dioxo-11α,15α-dihydroxy-1-acetoxymethyl-17,20-tetranor-16-p-fluorophenoxy-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 171. The optically active compound according to claim 157, 1,9-dioxo-11α,15α-dihydroxy-1-acetoxymethyl-18,20-trinor-17-phenyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 172. The optically active compound according to claim 157, nat-1,9-dioxo-11α,15-dihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-1-acetoxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 173. The optically active compound according to claim 157, nat-1,9-dioxo-11α,16-dihydroxy-16,17-tetramethylene-18,19,20-trinor-1-acetoxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 174. The optically active compound according to claim 157, nat-15S,16R-1,9-dioxo-11α,15-dihydroxy-15,16-trimethylene-1-acetoxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 175. The optically active compound according to claim 157, nat-15S,16S-1,9-dioxo-11α,15-dihydroxy-15,16-trimethylene-1-acetoxymethyl-5-cis-13-trans-prostadiene and the racemic mixture thereof.
 176. An optically active compound of the formula: ##STR185## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene and trans-vinylene; R₁ is a radical selected from the group consisting of: ##STR186## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of: ##STR187## wherein X is a divalent radical selected from the group consisting of: ##STR188## wherein R₅ is selected from the group consisting of C₁ -C₇ alkyl, hydrogen and a phenoxy group optionally substituted with a moiety selected from the group consisting of halogen, trifluoromethyl and C₁ -C₄ alkoxy, Y is a trivalent radical selected from the group consisting of: ##STR189## Z is a divalent radical selected from the group consisting of --O and --CH₂ --, m is zero or an integer from 1 to 4, inclusive, n is zero or an integer from 1 to 4, inclusive, with the proviso that the sum of m and n has the value of 1 to 4, s is zero or the integer 1, t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof.
 177. An optically active compound according to claim 176, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR190##
 178. An optically active compound according to claim 176, wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety ##STR191## wherein R is as previously defined.
 179. The optically active compound according to claim 177, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-trifluoromethylphenoxy-5-cis-13-trans-prostadiene-1-ethylene ketal and the mirror image thereof.
 180. The optically active compound according to claim 177, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-chlorophenoxy-5-cis-13-trans-prostadiene-1-ethylene ketal and the mirror image thereof.
 181. The optically active compound according to claim 177, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-17,20-tetranor-16-p-fluorophenoxy-5-cis-13-trans-prostadiene-1-ethylene ketal and the mirror image thereof.
 182. The optically active compound according to claim 177, 1,9-dioxo-11α,15α-dihydroxy-1-hydroxymethyl-18,20-trinor-17-phenyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the mirror image thereof.
 183. The optically active compound according to claim 178, nat-1,9-dioxo-11α,15-dihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 184. The optically active compound according to claim 178, nat-1,9-dioxo-11α,16-dihydroxy-16,17-tetramethylene-18,19,20-trinor-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 185. The optically active compound according to claim 178, nat-15S,16R-1,9-dioxo-11α,15-dihydroxy-15,16-trimethylene-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 186. The optically active compound according to claim 178, nat-15S,16S-1,9-dioxo-11α,15-dihydroxy-15,16-trimethylene-1-hydroxymethyl-5-cis-13-trans-prostadiene-1-ethylene ketal and the racemic mixture thereof.
 187. An optically active compound of the formula: ##STR192## wherein f is an integer from 2 to 4, inclusive; R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is ethylene or trans-vinylene, R₁ is selected from the group consisting of: ##STR193## wherein R is selected from the group consisting of C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of: ##STR194## wherein R₄ is selected from the group consisting of hydrogen and methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₇ is selected from the group consisting of C₂ -C₄ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl, p is an integer from 0 to 3, and q is 1 or 2, R₁₀ is selected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl, R₁₂ is selected from the group consisting of C₁ -C₄ alkyl, R₁₃ is C₃ -C₆ alkyl, X is a divalent radical selected from the group consisting of: ##STR195## wherein R₁₄ is selected from the group consisting of C₁ -C₇ alkyl, hydrogen and a phenoxy group optionally substituted from the group consisting of halogen, trifluoromethyl and C₁ -C₄ alkoxy, Y is a trivalent radical selected from the group consisting of: ##STR196## Z is a divalent radical selected from the group consisting of --O-- and --CH₂ --, m is zero or an integer from 1 to 4 inclusive, n is zero or an integer from 1 to 4, inclusive; with the proviso that the sum of m and n has the value of 1 to 4; s is zero or the integer 1, t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof. 